Cellular and Molecular Neurophysiology

Cellular and Molecular Neuro-physiology
Copyright
Dedication
Contributors
Foreword
Acknowledgments
1. Neurons
	1.1 Neurons have a cell body from which emerge two types of processes: the dendrites and the axon
		1.1.1 The somatodendritic tree is the neuron\'s receptive pole
		1.1.2 The axon and its collaterals are the neuron\'s transmitter pole
	1.2 Neurons are highly polarized cells with a differential distribution of organelles and proteins
		1.2.1 The soma is the main site of macromolecule synthesis
		1.2.2 The dendrites contain free ribosomes and synthesize some of their proteins
			1.2.2.1 Messenger RNA trafficking and local protein synthesis in dendrites
		1.2.3 The axon, to a large extent, lacks the machinery for protein synthesis
			1.2.3.1 Messenger RNA trafficking and local protein synthesis in axons
	1.3 Neurons are categorized based on their molecular signature, morphology, connectivity and physiology
		1.3.1 Cell transcriptomic analysis to assess cell identity
		1.3.2 Epigenetic profile to define cell diversity
		1.3.3 Combinatorial approach to categorize cell features
	1.4 Axonal transport allows bidirectional communication between the cell body and the axon terminals
		1.4.1 Demonstration of axonal transport
		1.4.2 Fast anterograde axonal transport is responsible for the movement of membranous organelles from cell body to axon terminals ...
			1.4.2.1 The pioneer living preparation
			1.4.2.2 Identification of the moving organelles and their substrates
			1.4.2.3 The role of ATP and kinesin
			1.4.2.4 Plus-end vesicle motors
		1.4.3 Retrograde axonal transport returns old membrane constituents, trophic factors, exogenous material to the cell body
			1.4.3.1 The minus-end motor(s)
			1.4.3.2 Functions of retrograde transport
		1.4.4 “Slow” anterograde axonal transport moves cytoskeletal proteins and cytosoluble proteins
			1.4.4.1 The different cytoskeletal elements are assembled and connected by bridges in the cell body
			1.4.4.2 The cytoskeletal proteins are transported in a soluble form or as isolated fibrils and assembled during their progression
			1.4.4.3 The transport of microtubules and neurofilaments is bidirectional, intermittent, asynchronous, and occurs at the rapid rate ...
		1.4.5 Axonal transport of mitochondria allows the turnover of mitochondria in axons and axon terminals
	1.5 Neurons connected by synapses form networks or circuits
		1.5.1 The circuit of the withdrawal medullary reflex
		1.5.2 The spinothalamic tract or anterolateral pathway is a somatosensory pathway
		1.5.3 How are the different noxious stimuli analyzed? Functional dissection of pain circuits with targeted ablative or optogeneti ...
		1.5.4 How is memory stored? The formation of engrams
			1.5.4.1 Engrams, the cellular basis of memory
			1.5.4.2 Maintenance of engram cell connectivity
	1.6 Summary: the neuron is an excitable and secretory cell presenting an extreme functional regionalization
		1.6.1 Regionalization of metabolic functions
		1.6.2 Regionalization of functions implicated in reception and transmission of electrical signals
		1.6.3 Regionalization of the secretory function
	Further reading
2. Neuron–glial cell cooperation
	2.1 Astrocytes are in a unique position between blood vessels and synapses
		2.1.1 Astrocytes are star-shaped cells characterized by the presence of glial filaments in their cytoplasm
		2.1.2 Astrocytes have complex morphological characteristics
		2.1.3 Astrocytes form an active bridge between the blood–brain barrier and neurons
		2.1.4 Astrocytes regulate the ionic composition of the extracellular fluid
		2.1.5 Astrocytes regulate the efficacy of synaptic transmission
	2.2 Oligodendrocytes form the myelin sheaths of axons in the central nervous system and contribute to cellular and functional p ...
		2.2.1 Myelin is a lipid-rich sheath enwrapping axons
			2.2.1.1 Myelin sheath is formed by extension and coiling of oligodendrocyte plasma membrane around the axon
			2.2.1.2 Myelin composition
		2.2.2 Myelin functions
			2.2.2.1 Myelin enables rapid conduction of action potentials
			2.2.2.2 Contribution of myelination to signal transmission efficiency
		2.2.3 Origin of myelination and myelination plasticity
			2.2.3.1 Origin of oligodendrocytes and myelination process
			2.2.3.2 Myelination is modulated by sensory experiences and by learning
			2.2.3.3 Myelin plasticity is required for optimal learning
			2.2.3.4 Postlesional plasticity
		2.2.4 Reciprocal interactions between neurons and oligodendroglia
			2.2.4.1 Oligodendroglial cells express a wide array of neurotransmitter/neuromodulator receptors
			2.2.4.2 Facilitation of conduction velocity by depolarization of oligodendrocytes
			2.2.4.3 Oligodendrocytes support axonal integrity
		2.2.5 Impact of myelin defects
			2.2.5.1 Susceptibility of oligodendrocytes to metabolic stress and aging
			2.2.5.2 Myelin alteration and psychiatric disorders/neurodegenerative diseases
	2.3 Microglial cells
		2.3.1 Microglial cells contribute to brain physiology and pathology
			2.3.1.1 Microglia are highly dynamic cells
			2.3.1.2 Microglia change their properties in pathological conditions to respond to injuries
			2.3.1.3 Microglia control adult neurogenesis
		2.3.2 Microglia control neuronal activity trough physical interaction and the release of soluble factors
			2.3.2.1 Microglia with physical interactions sculpt neuronal circuits, control neuronal excitability, and isolate brain injuries
			2.3.2.2 Microglia release soluble factors to control neuronal survival and activity
	Further reading
3. Ionic gradients, membrane potential and ionic currents
	3.1 There is an unequal distribution of ions across the neuronal plasma membrane. The notion of concentration gradient
		3.1.1 The plasma membrane separates two media of different ionic composition
		3.1.2 The unequal distribution of ions across the neuronal plasma membrane is kept constant by active transport of ions
		3.1.3 Na+, K+, Ca2+, and Cl− ions passively cross the plasma membrane through a particular class of transmembrane proteins—the ch ...
	3.2 There is a difference of potential between the two faces of the membrane, called membrane potential (Vm)
	3.3 Concentration gradients and membrane potential determine the direction of the passive movements of ions through ionic chann ...
		3.3.1 Ions passively diffuse down their concentration gradient
		3.3.2 Ions passively diffuse according to membrane potential
		3.3.3 In physiological conditions, ions passively diffuse according to the electrochemical gradient
			3.3.3.1 The equilibrium potential for a given ion, Eion
			3.3.3.2 The electrochemical gradient
	3.4 The passive diffusion of ions through an open channel creates a current
		3.4.1 Unitary current, iion
			3.4.1.1 Total current, Iion
			3.4.1.2 Roles of ionic currents (Table 3.1)
	3.5 A particular membrane potential, the resting membrane potential, Vrest
		3.5.1 When most of the channels open at rest are K+ channels, Vrest is close to EK
		3.5.2 In central neurons, K+, Cl−, and Na+ ion movements participate in resting membrane potential and Vrest is different from EK ...
	3.6 A simple equivalent electrical circuit for the membrane at rest
	3.7 Summary
	Appendix 3.1 The active transport of ions by pumps and transporters maintain the unequal distribution of ions (Fig. A3.1)
		A3.1.1 Pumps are ATPases that actively transport ions
			The Na/K-ATPase pump
			The Ca-ATPase pump
		A3.1.2 Transporters use the energy stored in the transmembrane electrochemical gradient of Na+, K+, H+ or other ions
			The Na–Ca transporter
			The Cl− transporters
			Neurotransmitter transporters
	Appendix 3.2 The passive diffusion of ions through an open channel
		What are the respective roles of the parts of the pore?
		Why are cations permeant and not anions?
		Why are K+ ions at least 1000 times more permeant than Na+ ions?
		What drives K+ ions to move on?
	Appendix 3.3 The Nernst equation
4. The voltage-gated channels of Na+ action potentials
	4.1 Properties of action potentials
		4.1.1 The different types of action potentials
		4.1.2 Na+ and K+ ions participate in the action potential of axons
			4.1.2.1 Na+ ions participate in the depolarization phase of the action potential
			4.1.2.2 K+ ions participate in the repolarization phase of the action potential
		4.1.3 Na+-dependent action potentials are all or none and propagate along the axon with the same amplitude
		4.1.4 Questions about the Na+-dependent action potential
	4.2 The depolarization phase of Na+-dependent action potentials results from the transient entry of Na+ ions through voltage-ga ...
		4.2.1 The Na+ channel consists of a principal large α-subunit with four internal homologous repeats and auxiliary β-subunits
		4.2.2 Membrane depolarization favors conformational change of the Na+ channel toward the open state; the Na+ channel then quickly ...
			4.2.2.1 Voltage-gated Na+ channels of the skeletal muscle fiber
			4.2.2.2 Rat brain Na+ channels
			4.2.2.3 The unitary current has a rectangular shape; the channel inactivates
			4.2.2.4 The unitary current is carried by a few Na+ ions
			4.2.2.5 The Na+ channel fluctuates between the closed, open and inactivated states
		4.2.3 The time during which the Na+ channel stays open varies around an average value, τo, called the mean open time
		4.2.4 The iNa–V relation is linear: The Na+ channel has a constant unitary conductance γNa
		4.2.5 The probability of the Na+ channel being in the open state increases with depolarization to a maximal level
		4.2.6 The macroscopic Na+ current (INa) has a steep voltage dependence of activation and inactivates within a few milliseconds
			4.2.6.1 The macroscopic Na+ current, INa, is the sum of the unitary currents, iNa, flowing through all the open Na+ channels of the ...
			4.2.6.2 The I–V relation is bell-shaped though the i–V relation is linear
			4.2.6.3 Activation and inactivation curves: the threshold potential
			4.2.6.4 Ionic selectivity of the Na+ channel
			4.2.6.5 Tetrodotoxin is a selective open Na+ channel blocker
		4.2.7 Segment S4, the region between segments S5 and S6, and the region between domains III and IV play a significant role in act ...
			4.2.7.1 The membrane-spanning segments S5 and S6 and the P-loop are membrane-associated and contribute to pore formation
			4.2.7.2 The S4 segment is the voltage sensor
			4.2.7.3 The cytoplasmic loop between domains III and IV contains the inactivation particle which, in a voltage-dependent manner, en ...
		4.2.8 Conclusion: the consequence of the opening of a population of N Na+ channels is a transient entry of Na+ ions which depolar ...
			4.2.8.1 Rapid activation of Na+ channels makes the depolarization phase sudden
			4.2.8.2 Rapid inactivation of Na+ channels makes the depolarization phase brief
	4.3 The Repolarization phase of the sodium-dependent action potential results from Na+ channel inactivation and partly from K+  ...
		4.3.1 The delayed rectifier K+ channel consists of four Kv α-subunits and auxiliary β-subunits
		4.3.2 Membrane depolarization favors the conformational change of the delayed rectifier channel toward the open state
			4.3.2.1 The function of the delayed rectifier channel is to transduce, with a delay, membrane depolarization into an exit of K+ ions
			4.3.2.2 Why do delayed rectifier Kv channels open slower than Nav channels?
		4.3.3 The open probability of the delayed rectifier channel is stable during a depolarization in the range of seconds
		4.3.4 The K+ channel has a constant unitary conductance γK
		4.3.5 The macroscopic delayed rectifier K+ current (IK) has a delayed voltage dependence of activation and inactivates within ten ...
			4.3.5.1 The delayed rectifier channels are selective to K+ ions
		4.3.6 Conclusion: during an action potential the consequence of the delayed opening of K+ channels is an exit of K+ ions, which r ...
	4.4 Sodium-dependent action potentials are initiated at the axon initial segment in response to a Membrane depolarization and t ...
		4.4.1 Summary on the Na+-dependent action potential
		4.4.2 Depolarization of the membrane to the threshold for voltage-gated Na+ channel activation has two origins
		4.4.3 The site of initiation of Na+-dependent action potentials is the axon initial segment
		4.4.4 The Na+-dependent action potential actively propagates along the axon up to axon terminals
			4.4.4.1 The propagation is active
			4.4.4.2 The propagation is unidirectional owing to Na+ channel inactivation
			4.4.4.3 The refractory periods between two action potentials
		4.4.5 Do the Na+ and K+ concentrations change in the extracellular or intracellular media during firing?
		4.4.6 Characteristics of the Na+-dependent action potential are explained by the properties of the voltage-gated Na+ channel
		4.4.7 The role of the Na+-dependent action potential is to evoke neurotransmitter release
	Further reading
5. The voltage-gated channels of Ca2+ action potentials: generalization
	5.1 Properties of Ca2+-dependent action potentials
		5.1.1 Ca2+ and K+ ions participate in the action potential of endocrine cells
			5.1.1.1 Ca2+ ions participate in the depolarization phase of the action potential
			5.1.1.2 K+ ions participate in the repolarization phase of the action potential
		5.1.2 Questions about Ca2+-dependent action potentials
	5.2 The transient entry of Ca2+ ions through voltage-gated Ca2+ channels is responsible for the depolarizing phase or the plate ...
		5.2.1 The voltage-gated Ca2+ channels are a diverse group of multisubunit proteins
			5.2.1.1 How to record the activity of Ca2+ channels in isolation
		5.2.2 The L-, N-, and P-type Ca2+ channels open at membrane potentials positive to −20 mV; they are high-threshold Ca2+ channels
			5.2.2.1 The L-type Ca2+ channel has a large conductance and inactivates very slowly with depolarization
			5.2.2.2 The N-type Ca2+ channel either inactivates with depolarization in the tens of milliseconds range or slowly inactivates; it  ...
			5.2.2.3 The P-type Ca2+ channel differs from the N channel by its pharmacology
		5.2.3 Macroscopic L-, N-, and P-type Ca2+ currents activate at a high threshold and inactivate with different time courses
			5.2.3.1 The I/V relations for L-, N- and P-type Ca2+ currents have a bell shape with a peak amplitude at positive potentials
			5.2.3.2 Activation–inactivation properties
			5.2.3.3 Voltage-gated Ca2+ channels show varying degrees of inactivation
			5.2.3.4 Calcium-dependent inactivation
	5.3 The repolarization phase of Ca2+-dependent action potentials results from the activation of K+ currents IK and IKCa
		5.3.1 The Ca2+-activated K+ currents are classified as big K (BK) channels and small K (SK) channels
		5.3.2 Ca2+ entering during the depolarization or the plateau phase of Ca2+-dependent action potentials activates KCa channels
	5.4 Calcium-dependent action potentials are initiated in axon terminals and in dendrites
		5.4.1 Depolarization of the membrane to the threshold for the activation of L-, N- and P-type Ca+ channels has two origins
		5.4.2 The role of the calcium-dependent action potentials is to provide a local and transient increase of [Ca2+]i to trigger secr ...
	5.5 A note on voltage-gated channels and action potentials
	Further reading
6. The chemical synapses
	6.1 The synaptic complex\'s three components: presynaptic element, synaptic cleft, and postsynaptic element
		6.1.1 The pre- and postsynaptic elements are morphologically and functionally specialized
		6.1.2 General functional model of the synaptic complex
		6.1.3 Complementarity between the neurotransmitter stored and released by the presynaptic element and the nature of receptors in  ...
			6.1.3.1 Targeting of receptors to a specific postsynaptic membrane
			6.1.3.2 Anchoring and clustering of receptors in the postsynaptic membrane
			6.1.3.3 Maintenance of synapses between neurons
			6.1.3.4 Dynamics of synapses between neurons
	6.2 The interneuronal synapses of the central nervous system
		6.2.1 In the CNS, the most common synapses are those where an axon terminal is the presynaptic element
		6.2.2 At low magnification, the axo-dendritic synaptic contacts display features implying various functions
		6.2.3 Interneuronal synapses display ultrastructural characteristics that vary between two extremes: types 1 and 2
	6.3 The neuromuscular junction is the group of synaptic contacts between the terminal arborization of a motor axon and a striat ...
		6.3.1 In the axon terminals, the synaptic vesicles are concentrated at the level of the electron-dense bars; they contain acetylc ...
		6.3.2 The synaptic cleft is narrow and occupied by a basal lamina which contains acetylcholinesterase
		6.3.3 Nicotinic receptors for acetylcholine are abundant in the crests of the folds in the postsynaptic membrane
		6.3.4 Mechanisms involved in the accumulation of postsynaptic cholinergic nicotinic receptors (nAChRs) in the postsynaptic muscul ...
	6.4 The synapse between the vegetative postganglionic neuron and the smooth muscle cell
		6.4.1 The presynaptic element is a varicosity of the postganglionic axon
		6.4.2 The width of the synaptic cleft is very variable
		6.4.3 The autonomous postganglionic synapse is specialized to ensure a widespread effect of the neurotransmitter
	6.5 Example of a neuroglandular synapse
	6.6 Summary
	Appendix 6.1 Neurotransmitters, agonists, and antagonists
		A6.1.1 Criteria to be satisfied before a molecule can be identified as a neurotransmitter
		A6.1.2 Types of neurotransmitters
			Acetylcholine: a quaternary amine
			Amino acids: glutamate, GABA (γ-aminobutyric acid), and glycine
			Monoamines
			Neuropeptides
		A6.1.3 Agonists and antagonists of a receptor
	Further reading
7. Neurotransmitter release
	7.1 The concept of vesicular release. Observations and questions
		7.1.1 The concept of vesicular release
		7.1.2 The synaptic vesicle cycle
		7.1.3 Questions
	7.2 The molecular machinery underlying the synaptic vesicle cycle
		7.2.1 Docking: A subpopulation of synaptic vesicles is docked to the active zone close to Ca2+ channels by means of specific pair ...
			7.2.1.1 Specific pairing of vesicular and plasma membrane proteins
			7.2.1.2 Docking of synaptic vesicles close to presynaptic Ca2+ channels
		7.2.2 Priming and fusion: the membrane of docked synaptic vesicles fuse with the plasma membrane of the active zone in response t ...
		7.2.3 SNAREs regulators
	7.3 The regulation of the intracellular Ca2+ concentration at active zones
		7.3.1 The presynaptic Na+ spike depolarizes the presynaptic membrane, opens presynaptic Ca2+ channels and triggers Ca2+ entry
			7.3.1.1 Is [Ca2+]i increase a prerequisite for transmitter release?
			7.3.1.2 When does Ca2+ enter the presynaptic element in response to a presynaptic spike?
			7.3.1.3 Which types of Ca2+ channels are involved in transmitter release?
		7.3.2 Presynaptic [Ca2+] increase is transient and restricted to micro- or nanodomains close to docked vesicles
			7.3.2.1 How does Ca2+ rise in a presynaptic terminal, uniformly or in domains?
			7.3.2.2 What is the Ca2+ sensor for neurotransmitter exocytosis?
			7.3.2.3 How is the topography of HVA Ca2+ channels and synaptic vesicles organized?
		7.3.3 Ca2+ clearance makes presynaptic [Ca2+]i increase transient: it shapes its amplitude and duration
			7.3.3.1 Extrusion of Ca2+ to the extracellular medium by the plasma membrane Ca-ATPase pump and by the Na–Ca exchanger
			7.3.3.2 Sequestration of Ca2+ ions in smooth endoplasmic reticulum and mitochondria
			7.3.3.3 Ca2+ buffering by cytosolic proteins
			7.3.3.4 The relative contribution of the clearance systems: example of Purkinje cells
	7.4 The different pools of synaptic vesicle
		7.4.1 The ready-releasable pool
			7.4.1.1 RRP size estimate using osmotic shocks, Ca2+ uncaging and long presynaptic depolarization
			7.4.1.2 RRP size estimate using action-potential evoked neurotransmitter release
			7.4.1.3 Heterogeneity of the RRP
		7.4.2 The recycling pool
		7.4.3 The reserve pool
		7.4.4 The superpool
	7.5 Pharmaclogy of neurotransmitter release
		7.5.1 Blockers of K+ currents
		7.5.2 Botulinum toxins
	7.6 Summary
	Appendix 7.1: Quantal nature of neurotransmitter release
	Appendix 7.2: Methods of neurotransmitter release measurements
	Appendix 7.3: Variance analysis and quantification of parameters of neurotransmitter release
	Appendix 7.4: Lipids as novel actors in neurotransmitter release
	Appendix 7.5: SNAREopathies
	Further reading
8. The ionotropic nicotinic acetylcholine receptors
	8.1 Observations
		8.1.1 Questions
	8.2 The torpedo or muscle nicotinic receptor of acetylcholine is a heterologous pentamer α2βγδ or α2βεδ
		8.2.1 Nicotinic receptors have a rosette shape with an aqueous pore in the center
		8.2.2 The four subunits of the nicotinic receptor are assembled as a pentamer
			8.2.2.1 The nicotinic receptor is composed of four glycopolypeptide subunits α, β, γ, δ or α, β, ε, δ
		8.2.3 Each α-subunit contains one acetylcholine receptor site located in the hydrophilic NH2-terminal domain
		8.2.4 The pore of the ion channel is lined by the M2 transmembrane segments of each of the five subunits
	8.3 Binding of two acetylcholine molecules favors conformational change of the protein toward the open state of the cationic ch ...
		8.3.1 Demonstration of the binding of two acetylcholine molecules
		8.3.2 The nicotinic channel has a selective permeability to cations: its unitary conductance is constant
			8.3.2.1 The nicotinic current reverses at 0mV
			8.3.2.2 The unitary conductance is constant
			8.3.2.3 The nicotinic channel is a cationic channel
			8.3.2.4 In which direction do Na+ and K+ ions cross the open nicotinic channel at different membrane potentials?
			8.3.2.5 Effect of a decrease in [Na+]e
			8.3.2.6 Substitution of K+ ions for extracellular Na+ ions
			8.3.2.7 Mutations in the M2 membrane-spanning segment can convert ion selectivity from cationic to anionic
		8.3.3 The time during which the channel stays open varies around an average value τo, the mean open time, and is a characteristic ...
			8.3.3.1 τo is a characteristic of the nicotinic receptor channel type
	8.4 The nicotinic receptor desensitizes
		8.4.1 Generalization
	8.5 nAChR-mediated synaptic transmission at the neuromuscular junction
		8.5.1 Miniature and endplate synaptic currents are recorded at the neuromuscular junction
			8.5.1.1 Miniature currents
			8.5.1.2 Motor endplate current
		8.5.2 Synaptic currents are the sum of unitary currents appearing with variable delays and durations
	8.6 Nicotinic transmission pharmacology
		8.6.1 Nicotinic agonists of muscle nAChRs
		8.6.2 Competitive nicotinic antagonists
		8.6.3 Channel blockers
		8.6.4 Acetylcholinesterase inhibitors
	8.7 Neuronal nicotinic receptors and interneuronal nicotinic synaptic transmission
		8.7.1 Neuronal nicotinic receptors are homo- or heteropentamers composed of α or α and β subunits
		8.7.2 Nicotinic transmission at neuronal synapses
		8.7.3 Nicotinic transmission pharmacology at neuronal synapses
	8.8 Summary
	Further reading
9. The ionotropic GABAA receptor
	9.1 Observations and questions
	9.2 GABAA receptors are hetero-oligomeric proteins with a structural heterogeneity
		9.2.1 The diversity of GABAA receptor subunits
		9.2.2 Subunit composition of native GABAA receptors and their binding characteristics
	9.3 Binding of two GABA molecules leads to a conformational change of the GABAA receptor into an open state; the GABAA receptor ...
		9.3.1 GABA-binding site
		9.3.2 Evidence for the binding of two GABA molecules
		9.3.3 The GABAA channel is selectively permeable to Cl− ions
		9.3.4 The single-channel conductance of GABAA channels is constant in symmetrical Cl− solutions, but varies as a function of pote ...
		9.3.5 Mean open time of the GABAA channel
			9.3.5.1 Brief openings (triangles)
			9.3.5.2 Bursts of openings (open circles)
			9.3.5.3 Silent periods
		9.3.6 The GABAA receptor desensitizes
	9.4 Pharmacology of the GABAA receptor
		9.4.1 Ligands at the GABA-binding site: agonists and competitive antagonists of the GABAA receptor
		9.4.2 Ligand at the channel pore: picrotoxin reversibly decreases total GABAA current; it is a noncompetitive antagonist of the G ...
		9.4.3 Ligands of the high-affinity site for benzodiazepines are positive, negative, or silent modulators of a subset of GABAA rec ...
		9.4.4 Benzodiazepines and β-carbolines bind to the GABAA receptor at a specific high-affinity binding site
			9.4.4.1 Benzodiazepines potentiate the total GABAA current; they are positive allosteric modulators of the GABAA receptor
			9.4.4.2 β-Carbolines reversibly decrease the total GABAA current; they bind at the benzodiazepine high-affinity site and are negati ...
		9.4.5 Other ligands: barbiturates and neurosteroids are positive allosteric modulators that bind at ill-defined binding sites of  ...
			9.4.5.1 Barbiturates and neurosteroids potentiate the GABAA response
	9.5 GABAA receptor-mediated synaptic transmission
		9.5.1 The GABAergic synapse
		9.5.2 The synaptic GABAA-mediated current is the sum of unitary currents appearing with variable delays and durations
			9.5.2.1 From single GABAA current to IPSC
			9.5.2.2 Single-spike IPSC
			9.5.2.3 Single-spike IPSP
		9.5.3 Generalization: the consequences of the synaptic activation of GABAA receptors depend on the relative values of ECl and Vm  ...
			9.5.3.1 When ECl is more hyperpolarized than Vrest, GABAA receptor activation leads to a hyperpolarizing postsynaptic potential and ...
			9.5.3.2 When ECl is close to Vrest, activation of GABAA receptor leads to a “silent inhibition” of postsynaptic activity
			9.5.3.3 When ECl is more depolarized than Vrest but below the threshold for action potential generation, GABAA receptor activation  ...
			9.5.3.4 When ECl is more depolarized than Vrest and above the threshold for action potential generation, GABAA receptor activation  ...
		9.5.4 What shapes the decay phase of GABAA-mediated currents?
	9.6 Summary
		9.6.1 How does GABAA receptor mediate the binding of GABA into a transient hyperpolarization of the membrane?
		9.6.2 Do benzodiazepines and barbiturates act directly on GABAA receptors? Are there selective and distinct binding sites on the  ...
	Appendix 9.1 Mean open time and mean burst duration of the GABAA single-channel current
	Appendix 9.2 Noninvasive measurements of membrane potential and of the reversal potential of the GABAA current using cell-a ...
	Further reading
10. The ionotropic glutamate receptors
	10.1 There are three different types of ionotropic glutamate receptors. They have a common structure and all participate in fast ...
		10.1.1 Ionotropic glutamate receptors are named after their selective or preferential agonist. They share a common structure
		10.1.2 The ligand-binding domain
		10.1.3 The three ionotropic receptors participate in fast glutamatergic synaptic transmission
	10.2 AMPA receptors are an ensemble of cationic receptor-channels with different permeabilities to Ca2+ ions
		10.2.1 The diversity of AMPA receptors results from subunit combination, alternative splicing and posttranscriptional nuclear editing
		10.2.2 The native AMPA receptor is permeable to cations and has a unitary conductance of 8pS
		10.2.3 AMPA receptors are permeable to Na+, K+, and Ca2+ ions unless the edited form of GluA2 is present; in the latter case, AMPA ...
		10.2.4 AMPA current through GluA2-lacking AMPA receptors displays inward rectification
		10.2.5 Summary
	10.3 Kainate receptors are an ensemble of cationic receptor channels with different permeabilities to Ca2+ ions
		10.3.1 The diversity of kainate receptors
		10.3.2 Native kainate receptors are permeable to cations
	10.4 NMDA receptors are cationic-receptor-channels highly permeable to Ca2+ ions; they are blocked by Mg2+ ions at voltages clos ...
		10.4.1 Molecular biology of NMDA receptors
		10.4.2 Native NMDA receptors have a high unitary conductance of 50pS or a lower one of 17–35pS depending on subunit composition
		10.4.3 The NMDA channel is highly permeable to monovalent cations and to Ca2+
			10.4.3.1 What does molecular biology tell us about Ca2+ permeability?
		10.4.4 NMDA channels are blocked by physiological concentrations of extracellular Mg2+ ions; this block is voltage-dependent
			10.4.4.1 Mechanism of action of Mg2+ ion block: A hypothesis
			10.4.4.2 Why is the NMDA channel permeable to Ca2+ ions and blocked by Mg2+ ions?
			10.4.4.3 What does molecular biology tell us about Mg2+ block?
			10.4.4.4 Why do channel properties fundamental to NMDAR function (Mg2+ block, Ca2+ permeability, and single channel conductance) var ...
		10.4.5 Glycine is a coagonist of NMDA receptors
		10.4.6 Conclusions on NMDA receptors
	10.5 Synaptic responses to glutamate are mediated by NMDA and nonNMDA receptors
		10.5.1 Glutamate receptors are colocalized in the postsynaptic membrane of glutamatergic synapses
		10.5.2 The glutamatergic postsynaptic current is inward and can have at least two components in the absence of extracellular Mg2+ ions
			10.5.2.1 Which receptor channels contribute to the nonNMDA component of the synaptic current?
		10.5.3 The glutamatergic postsynaptic depolarization has at least two components in the absence of extracellular Mg2+ ions
		10.5.4 Synaptic depolarization recorded in physiological conditions: factors controlling NMDA receptor activation
			10.5.4.1 When NMDA and nonNMDA receptors coexist in the postsynaptic membrane
			10.5.4.2 When NMDA receptors are the only receptors present in the postsynaptic membrane
	10.6 Summary
		10.6.1 Do all ionotropic glutamate receptors have the same properties; for example, the same sensitivity to glutamate, the same io ...
		10.6.2 Do all these receptors have coagonists acting at modulatory sites?
		10.6.3 What are the exact conditions of the activation of the different iGluRs?
	Further reading
11. The metabotropic GABAB receptors
	11.1 Introduction
	11.2 GABAB receptors were originally discovered because of their insensitivity to bicuculline and their sensitivity to baclofen
	11.3 Structure of the GABAB receptor
		11.3.1 GABAB receptors belong to family 3G protein-coupled receptors
			11.3.1.1 Cloning of the GABAB receptor
		11.3.2 GABAB receptors are heterodimers
			11.3.2.1 GABAB1 receptors are nonfunctional
			11.3.2.2 Fully functional GABAB receptors require coupling between GABAB1 and GABAB2
		11.3.3 Surface expression of GABAB receptors requires coupling between GABAB1 and GABAB2
		11.3.4 The GABA-binding site is in the extracellular amino-terminal domain of GABAB1
		11.3.5 GABAB2 subunits couple to inhibitory G proteins
		11.3.6 Molecular diversity of GABAB receptors arises from GABAB1 isoforms
		11.3.7 GABAB receptors are located throughout the brain at both presynaptic and postsynaptic sites
		11.3.8 GABAB receptor properties are regulated by auxiliary subunits
	11.4 GABAB receptor pharmacology
	11.5 Summary
	11.6 GABAB receptors are G‐protein‐coupled to a variety of different effector mechanisms
		11.6.1 GABAB receptors regulate the activity of adenylyl cyclase
			11.6.1.1 GABAB receptors are negatively coupled to adenylyl cyclase through inhibitory G proteins
			11.6.1.2 GABAB receptors facilitate neurotransmitter-mediated activation of adenylyl cyclase
		11.6.2 GABAB receptor activation inhibits voltage-dependent calcium channels
			11.6.2.1 Heterodimeric GABAB receptors directly inhibit calcium currents
			11.6.2.2 Inhibition of calcium channels is dependent upon the βγ subunit of Gi/Go proteins
			11.6.2.3 GABAB receptors inhibit calcium channels by altering their voltage-dependence
		11.6.3 GABAB receptors activate potassium channels
			11.6.3.1 GABAB receptors couple to inwardly rectifying (Kir3) potassium channels
			11.6.3.2 GABAB receptors are coupled to potassium channels via inhibitory G proteins
			11.6.3.3 GABAB receptors are directly coupled to potassium channels by βγ subunits of G proteins
			11.6.3.4 GABAB receptors and Kir3 channels form a macromolecular signaling complex in lipid rafts
			11.6.3.5 GABAB receptor-activated potassium channels display flickering behavior
	11.7 Summary
	11.8 The functional role of GABAB receptors in synaptic activity
		11.8.1 Postsynaptic GABAB receptors produce an inhibitory postsynaptic current
			11.8.1.1 The kinetics of the GABAB receptor-mediated response are slow
			11.8.1.2 GABAB receptors are more sensitive than GABAA receptors to GABA
			11.8.1.3 The GABAB IPSC produces inhibition by hyperpolarizing the neuronal membrane
		11.8.2 Presynaptic GABAB receptors inhibit the release of many different transmitters
			11.8.2.1 Presynaptic GABAB receptors inhibit the release of GABA
			11.8.2.2 The time course of the depression of GABA release is similar to the time course of the postsynaptic GABAB IPSC
			11.8.2.3 GABAB receptors suppress transmitter release by directly targeting the release machinery and by inhibiting voltage-dependen ...
	11.9 Summary
	Further reading
12. The metabotropic glutamate receptors
	12.1 The identification of the metabotropic glutamate receptor subtypes
	12.2 How do metabotropic glutamate receptors carry out their function? Structure–function studies of metabotropic glutamate rece ...
	12.3 How to identify selective compounds acting at the metabotropic glutamate receptor—toward the Development of new therapeutic ...
	12.4 What biochemical means do metabotropic glutamate receptors utilize to elicit physiological changes in the nervous system? S ...
	12.5 How is the activity of metabotropic glutamate receptors modulated? Studies of mGluR desensitization
	12.6 Metabotropic glutamate receptors modulate neuronal excitability
	12.7 Metabotropic glutamate receptors mediate and modulate synaptic transmission
	12.8 Pre- and postsynaptic functional assembly of metabotropic glutamate receptors
	12.9 Physiological roles of metabotropic glutamate receptor—a study of knockout models
	12.10 Summary
	Further reading
13. The metabotropic olfactory receptors
	13.1 General view on olfactory transduction
		13.1.1 The olfactory sensory neurons are the key players of olfactory transduction
		13.1.2 Pioneering experiments
		13.1.3 Questions
		13.1.4 Olfactory transduction: An overview
	13.2 Odorants bind to specific odorant receptors
		13.2.1 Odorants diffuse through the extracellular mucous matrix before interacting with olfactory receptor neurons
		13.2.2 Odorant recognition is achieved by the odorant receptors, a family of G-protein coupled receptors
		13.2.3 The activation of odorant receptors leads to the activation of a Golf protein
		13.2.4 The G-protein Golf activates adenylyl cyclase that converts ATP to 3′,5′- cyclic AMP
	13.3 The second messenger cAMP opens a cyclic nucleotide gated channel and generates an inward cationic current
		13.3.1 The olfactory cyclic nucleotide-gated channel is a heterotetrameric ligand-gated channel
		13.3.2 Cyclic AMP directly opens the olfactory cyclic nucleotide-gated channel
		13.3.3 The unitary cAMP-induced current reverses around 0mV
			13.3.3.1 The unitary CNG conductance is constant in the absence of divalent cations
			13.3.3.2 Is the cyclic nucleotide-gated channel a nonspecific cationic channel?
		13.3.4 The activation of N cyclic nucleotide-gated channels evokes an inward depolarizing current carried by cations
			13.3.4.1 Intracellular cAMP induces a dose-dependent inward current
			13.3.4.2 The cAMP-gated current is generated in cilia
			13.3.4.3 The cAMP-gated current is carried by the cations Na+, K+ and Ca2+
	13.4 The third messenger, intracellular Ca2+ ions, activates a calcium-sensitive chloride channel and generates an inward chlori ...
		13.4.1 The hypothesis of a Ca2+-activated current involved in olfactory transduction
		13.4.2 The olfactory Ca2+-activated chloride channel belongs to the TMEM16 family
		13.4.3 Activation of Ca2+-gated chloride channels by Ca2+ entry through cAMP-gated cationic channels generates an inward depolariz ...
	13.5 The transduction current is transient and shows adaptation
		13.5.1 The second messenger cAMP and the third messenger Ca2+ ions are rapidly degraded or cleared out
		13.5.2 Intracellular Ca2+ ions desensitize the cAMP-gated channel: Odor adaptation
	13.6 Coding of odorant concentration
		13.6.1 The odorant-induced inward currents depolarize the membrane of olfactory receptors: the generator potential
		13.6.2 The odorant-induced depolarization takes place in the cilia; spikes are initiated in the soma–initial axon segment, and the ...
	13.7 Summary
	Further reading
14. Somatodendritic processing of postsynaptic potentials I: passive properties of dendrites
	14.1 Propagation of excitatory and inhibitory postsynaptic potentials through the dendritic arborization
		14.1.1 The complexity of synaptic organization (Fig. 14.1)
			14.1.1.1 Presynaptic complexity
			14.1.1.2 Postsynaptic complexity
			14.1.1.3 Complexities of the propagation of postsynaptic action potentials
		14.1.2 Passive decremental propagation of postsynaptic potentials
		14.1.3 Passive and nondecremental propagation of postsynaptic potentials
	14.2 Summation of excitatory and inhibitory postsynaptic potentials
		14.2.1 Linear and nonlinear summation of excitatory postsynaptic potentials
			14.2.1.1 Linear summation of excitatory postsynaptic potentials
			14.2.1.2 Nonlinear summation of excitatory postsynaptic potentials
		14.2.2 Linear and nonlinear summation of inhibitory postsynaptic potentials
		14.2.3 The integration of excitatory and inhibitory postsynaptic potentials partly determines the configuration of the postsynapti ...
			14.2.3.1 Integration of depolarizing (excitatory) postsynaptic potentials with hyperpolarizing (inhibitory) postsynaptic potentials
			14.2.3.2 Integration of depolarizing (excitatory) postsynaptic potentials and silent (inhibitory) postsynaptic potentials
			14.2.3.3 Integration of depolarizing (excitatory) postsynaptic potentials and depolarizing inhibitory postsynaptic potentials
	14.3 Summary
	Further reading
15. Subliminal voltage-gated currents of the somatodendritic membrane
	15.1 Observations and questions
	15.2 The subliminal voltage-gated currents that depolarize the membrane
		15.2.1 The persistent inward Na+current, INaP
			15.2.1.1 Structure of the main channel subunit
			15.2.1.2 Gating properties and ionic nature
			15.2.1.3 Pharmacology
			15.2.1.4 Summary
		15.2.2 The low-threshold transient Ca2+ current, ICaT (Cav3 channels)
			15.2.2.1 Structure of the main channel subunit
			15.2.2.2 Single-channel conductance
			15.2.2.3 Gating properties and ionic nature
			15.2.2.4 Pharmacology
			15.2.2.5 Summary
		15.2.3 The hyperpolarization-activated cationic current, Ih, If, IQ (HCN channels)
			15.2.3.1 Structure of the main channel subunit
			15.2.3.2 Single-channel current
			15.2.3.3 Gating properties and ionic nature
			15.2.3.4 Pharmacology
			15.2.3.5 Summary
	15.3 The subliminal voltage-gated currents that hyperpolarize the membrane
		15.3.1 The rapidly activating and fast inactivating A-type K+ current: IA or (Kv4/KCND channels)
			15.3.1.1 Structure of the main channel subunit
			15.3.1.2 Gating properties and ionic nature
			15.3.1.3 Pharmacology
			15.3.1.4 Summary
		15.3.2 The rapidly activating and slowly inactivating K+ current, ID
			15.3.2.1 Gating properties
			15.3.2.2 Pharmacology
			15.3.2.3 Summary
		15.3.3 The K+ currents activated by intracellular Ca2+ ions, IKCa
		15.3.4 The K+ current sensitive to muscarine, IM (Kv7/KCNQ channels)
			15.3.4.1 Structure of Kv7/KCNQ channels
			15.3.4.2 Gating properties and ionic nature
			15.3.4.3 Inhibition by muscarinic receptors agonists
			15.3.4.4 Pharmacology
			15.3.4.5 Summary
		15.3.5 The inward rectifier K+ current, IKir (Kir channels)
			15.3.5.1 Structure of the main channel subunit
			15.3.5.2 Gating properties and ionic nature
			15.3.5.3 Pharmacology
			15.3.5.4 Summary
	15.4 General conclusion
	Further reading
16. Somatodendritic processing of postsynaptic potentials II. Role of subthreshold voltage-gated currents
	16.1 Persistent Na+ channels are present in the axosomatic region of neocortical neurons; INaP boosts EPSPs
		16.1.1 Persistent Na+ channels are present in the dendrites and soma of pyramidal neurons of the neocortex
			16.1.1.1 Dendritic recordings
			16.1.1.2 Somatic recordings
		16.1.2 Are persistent Na+ channels activated by EPSPs? Where does INaP boost EPSP amplitude, in the dendrites, in the soma, or in  ...
	16.2 T-type Ca2+ channels are present in the dendrites of cortical neurons; ICaT boosts EPSPs
		16.2.1 T-type Ca2+ channels are present in the dendrites of pyramidal neurons of the hippocampus
		16.2.2 Dendritic T-type Ca2+ channels are activated by EPSPs; in turn, ICaT boosts EPSPs amplitude
	16.3 The hyperpolarization-activated cationic channels are present in dendrites of cortical pyramidal neurons; Ih has a dual act ...
		16.3.1 HCN channels are not homogenously expressed in dendrites of cortical pyramidal neurons
		16.3.2 Activation of dendritic HCN channels decreases or increases EPSPs amplitude depending on their density
	16.4 A-type K+ channels are present in the dendrites of hippocampal neurons; IA attenuates EPSPs
		16.4.1 A-type K+ channels are expressed in the dendrites of hippocampal pyramidal neurons
		16.4.2 A-type K+ current attenuates subthreshold EPSPs generated in the dendrites
	16.5 Functional consequences
	16.6 Conclusions
	Further reading
17. Somatodendritic processing of postsynaptic potentials III. Role of high-voltage–activated currents
	17.1 High-voltage–activated Na+ and/or Ca2+ channels are present in the dendritic membrane of some CNS neurons, but are they dis ...
		17.1.1 High-voltage–activated Na+ channels are present in the dendrites of some neurons
			17.1.1.1 Pyramidal neurons of the hippocampus
			17.1.1.2 Pyramidal neurons of the neocortex
			17.1.1.3 Dopaminergic neurons of the pars compacta of the substantia nigra
			17.1.1.4 Purkinje cells of the cerebellar cortex
			17.1.1.5 Conclusions
		17.1.2 Dendritic Na+ channels are opened by backpropagating axosomatic Na+ action potentials
			17.1.2.1 Pyramidal neurons of the neocortex
			17.1.2.2 Dopaminergic neurons of the substantia nigra pars compacta
			17.1.2.3 Purkinje cells
			17.1.2.4 Conclusions
	17.2 High-voltage–activated Ca2+ channels are present in the dendritic membrane of some CNS neurons, but are they distributed wi ...
		17.2.1 High-voltage–activated Ca2+ channels are present in the dendrites of some neurons
			17.2.1.1 Purkinje cells of the cerebellar cortex
			17.2.1.2 Pyramidal neurons of the hippocampus
			17.2.1.3 Conclusions
		17.2.2 High-voltage–activated Ca2+ channels of Purkinje cell dendrites are opened by climbing fiber EPSP; this initiates Ca2+ acti ...
		17.2.3 Dendritic high-voltage–activated Ca2+ channels are opened by backpropagating Na+ action potentials in pyramidal neurons of  ...
			17.2.3.1 Pyramidal neurons of the hippocampus
			17.2.3.2 Conclusions
	17.3 Functional consequences
		17.3.1 Amplification of distal synaptic responses by dendritic HVA currents counteracts their attenuation due to passive propagati ...
		17.3.2 Active backpropagation of Na+ spikes in the dendritic tree depolarizes the dendritic membrane, with multiple consequences
			17.3.2.1 A retrograde signal that activates voltage-sensitive dendritic Ca2+ channels
			17.3.2.2 A retrograde signal that amplifies NMDA-mediated synaptic currents
			17.3.2.3 A retrograde signal that shunts ongoing synaptic integration
		17.3.3 Initiation of Ca2+ spikes in the dendritic tree of Purkinje cells evokes a widespread intradendritic [Ca2+] increase
	17.4 Conclusions
	Further reading
18. Firing patterns of neurons
	18.1 Spiny projection neurons of the striatum
		18.1.1 Spiny projection neurons have a hyperpolarized resting membrane potential due to an inward rectifier K+ current
		18.1.2 When activated by a depolarizing current pulse, the response of spiny projection neurons in vitro is a long-latency regular ...
		18.1.3 When recorded in vivo, in freely moving rodents, the activity of spiny projection neurons varies with the arousal state of  ...
			18.1.3.1 SPN irregular firing during wakefulness
			18.1.3.2 SPN oscillatory firing during slow-wave sleep
			18.1.3.3 SPN silent membrane oscillations during paradoxical sleep
			18.1.3.4 Summary
	18.2 Inferior olivary cells
		18.2.1 Inferior olivary cells are mainly silent at rest in vitro but generate bursts of spikes in response to spontaneous afferent ...
		18.2.2 When depolarized, inferior olivary cells oscillate at a low frequency (3–6Hz) in vitro
		18.2.3 When hyperpolarized, inferior olivary cells oscillate at a higher frequency (8–10Hz) in vitro
		18.2.4 In vivo, in anesthetized rats, the membrane potential of inferior olivary cells spontaneously oscillates
	18.3 Purkinje cells of the cerebellar cortex
		18.3.1 Purkinje cells present an intrinsic tonic firing that depends on a persistent Na+current
		18.3.2 Purkinje cells respond to climbing fiber activation by a complex spike
		18.3.3 Purkinje cells generate a complex activity in vivo
			18.3.3.1 Summary
	18.4 Thalamic and subthalamic neurons
		18.4.1 The intrinsic tonic (single-spike) mode depends on a persistent Na+ current
		18.4.2 The bursting mode depends on a cascade of subthreshold inward currents: Ih, ICaT, ICAN
		18.4.3 The transition from one mode to the other is triggered by synaptic inputs
	18.5 Summary
	Further reading
19. Synaptic plasticity
	19.1 Short-term potentiation: example of the cholinergic synaptic response of muscle cell to motoneuron stimulation
	19.2 Long-term potentiation: example of the glutamatergic synaptic response of pyramidal neurons of the CA1 region of the hippoc ...
		19.2.1 The Schaffer collaterals are axon collaterals of CA3 pyramidal neurons which form glutamatergic excitatory synapses with de ...
		19.2.2 Observation of the long-term potentiation of the Schaffer collateral-mediated EPSP
			19.2.2.1 Is LTP restricted to the synapses that have been tetanized?
		19.2.3 Long-term potentiation of the glutamatergic EPSP recorded in CA1 pyramidal neurons results from an increase of synaptic eff ...
			19.2.3.1 Does LTP result from a nonspecific change of postsynaptic cell excitability?
			19.2.3.2 Does LTP result from an increase in the number of stimulated axons?
			19.2.3.3 LTP is an increase of synaptic strength
			19.2.3.4 LTP consists of two phases: induction and maintenance
		19.2.4 Induction of LTP results from a transient enhancement of glutamate release and a rise in postsynaptic intracellular Ca2+ co ...
			19.2.4.1 Why is tetanic stimulation necessary to induce LTP? What does tetanic stimulation add to a single shock stimulation?
			19.2.4.2 What does induce postsynaptic depolarization?
			19.2.4.3 What is the role of postsynaptic NMDA receptors activation?
			19.2.4.4 For how long must [Ca2+]i remain increased in the postsynaptic element to trigger LTP?
			19.2.4.5 The hypothetical model for LTP induction
				19.2.4.5.1 Before tetanus
				19.2.4.5.2 During tetanus
			19.2.4.6 Metabotropic glutamate receptors are modulators that regulate the threshold of induction of NMDAR-dependent LTP
		19.2.5 Expression of LTP (also called maintenance) involves a persistent enhancement of the AMPA component of the EPSP
			19.2.5.1 The Ca2+ signal is translated into an increase in synaptic strength by biochemical pathways
			19.2.5.2 Expression of LTP involves the phosphorylation and persistent upregulation of AMPA receptors
		19.2.6 Multiple ways to induce LTP, multiple forms of LTP, and multiple ways to block LTP induction
		19.2.7 Summary: principal features of LTP in the Schaffer collateral–pyramidal cell glutamatergic transmission
	19.3 Long-term depression: example of the glutamatergic synaptic response of Purkinje cells of the cerebellum to parallel fiber  ...
		19.3.1 The long-term depression of a postsynaptic response (EPSC or EPSP) is a decrease of synaptic efficacy
		19.3.2 Induction of LTD requires a rise in postsynaptic intracellular Ca2+ concentration and the activation of postsynaptic AMPA r ...
			19.3.2.1 [Ca2+]i rises during costimulation
			19.3.2.2 LTD of the response to parallel fiber is not observed when the parallel fibers are stimulated alone at 1–4Hz; what adds the ...
			19.3.2.3 LTD of the response to parallel fiber is not observed when the climbing fiber is stimulated alone at 1–4Hz; what adds the p ...
		19.3.3 The expression of LTD involves a persistent desensitization of postsynaptic AMPA receptors
		19.3.4 Second messengers are required for LTD induction
		19.3.5 The different ways to induce or block cerebellar LTD
		19.3.6 Summary: principal features of LTD in parallel-fiber/Purkinje cell glutamatergic transmission
	19.4 Short- and long-term depression mediated by endogenous cannabinoids
		19.4.1 Endogenous cannabinoids are retrograde mediators of the depolarization-induced suppression of inhibition: a short-term plas ...
			19.4.1.1 Observation of the depolarization-induced suppression of inhibition
			19.4.1.2 The depolarization-induced suppression of inhibition requires a postsynaptic rise of intracellular calcium concentration
			19.4.1.3 The depolarization-induced suppression of inhibition results from a transient suppression of GABA release
			19.4.1.4 Endocannabinoid acts as a retrograde messenger in the depolarization-induced suppression of inhibition
			19.4.1.5 Functional significance of the depolarization-induced suppression of inhibition
		19.4.2 Endogenous cannabinoids are retrograde mediators of long-term synaptic depression
		19.4.3 Synaptic logic of endocannabinoid-LTD: retrograde signaling and the perisynaptic signalosome
			19.4.3.1 eCB-LTD requires a postsynaptic rise of intracellular calcium concentration
			19.4.3.2 eCB-LTD requires the engagement of postsynaptic metabotropic receptors
			19.4.3.3 eCB signaling results from a specific postsynaptic macromolecular complex
			19.4.3.4 eCB are retrograde messenger in LTD
		19.4.4 The different ways to induce or block eCB-LTD
		19.4.5 Summary: principal features of endocannabinoid LTD
	19.5 Spike-timing-dependent plasticity, a long-term plasticity induced by relative timing between pre- and postsynaptic spikes
		19.5.1 Hebbian STDP: induction of LTP by positive correlation and of LTD by negative correlation
		19.5.2 The diversity of STDP: example of the corticostriatal glutamatergic synapse
		19.5.3 Cell-specific corticostriatal STDP rules rely on different molecular mechanisms
		19.5.4 The STDP rule
		19.5.5 Summary: principal features of STDP
	19.6 The homeostatic plasticity example of the synaptic scaling at the glutamatergic synapses of the neocortex
		19.6.1 Up-scaling of excitatory synaptic strength induced by chronic blockade of network activity
		19.6.2 Down-scaling of excitatory synaptic strength induced by chronic enhancement of network activity
		19.6.3 Synaptic scaling also affects inhibitory synaptic transmission
		19.6.4 Summary: principal features of homeostatic synaptic scaling
	Further reading
20. The adult hippocampal network
	20.1 Observations and questions
		20.1.1 What is a network?
		20.1.2 Are networks completely different from one nucleus to another or are there some fundamental principles of organization?
		20.1.3 Does the precise knowledge of intrinsic and extrinsic connections as well as the firing patterns of neurons allow us to exp ...
	20.2 The hippocampal circuitry
		20.2.1 Ammon\'s horn
			20.2.1.1 Pyramidal neurons use glutamate as a neurotransmitter
			20.2.1.2 Several types of inhibitory interneurons innervate pyramidal neurons; they use GABA as a neurotransmitter
		20.2.2 The dentate gyrus
			20.2.2.1 The granular cells use glutamate as a neurotransmitter
			20.2.2.2 Several types of inhibitory interneurons innervate granular cells; they use GABA as a neurotransmitter and their cell body  ...
		20.2.3 Pyramidal neurons and granular cells form a tri-neural excitatory circuit
			20.2.3.1 Extrinsic afferences to projection neurons and interneurons
	20.3 Activation of Interneurons evokes inhibitory gabaergic responses in postsynaptic pyramidal cells
		20.3.1 Experimental protocol to study pairs of neurons
		20.3.2 Unitary inhibitory postsynaptic currents evoked by different types of interneurons are all GABAAR-mediated but have differe ...
			20.3.2.1 Whole-cell patch recordings
			20.3.2.2 Unitary IPSCs evoked by different types of interneurons are all mediated by GABAA receptors
			20.3.2.3 Proximally and distally generated unitary IPSCs have different kinetic parameters
		20.3.3 GABAAR-mediated IPSCs generate IPSPs in postsynaptic pyramidal cells
		20.3.4 GABABR-mediated IPSPs are also recorded in pyramidal neurons in response to strong interneuron stimulation
	20.4 Activation of Pyramidal neurons evokes excitatory glutamatergic responses in postsynaptic interneurons and in other pyramid ...
		20.4.1 Pyramidal neurons evoke AMPAR-mediated EPSPs in interneurons
		20.4.2 EPSPs in interneurons lead to feedback inhibition of pyramidal neurons
		20.4.3 CA3 pyramidal neurons are monosynaptically connected via glutamatergic synapses
		20.4.4 Overview of intrinsic hippocampal circuits
	20.5 Oscillations in the hippocampal network: example of sharp waves and ripples
	20.6 Coding properties of CA1 pyramidal neurons during spatial exploration
		20.6.1 CA1 pyramidal neurons behave as place cells during the exploration of a space by an animal
		20.6.2 Intracellular determinants of place cells activation
		20.6.3 Spikelets contribute to place cells firing
		20.6.4 Intrinsic excitability gates place cell firing
		20.6.5 Plateau potentials contribute to place cell firing and could induce synaptic plasticity
	Further reading
21. Morphogenesis and maturation of the hippocampal network
	21.1 Hippocampal circuits are sculpted by development
		21.1.1 Early patterning of the developing hippocampus is regulated by key molecular factors
			21.1.1.1 How can different subregions be differentiated during development?
		21.1.2 During the process of neurogenesis, neural stem cells divide and differentiate at specific times and locations
		21.1.3 Cell migration in the hippocampus presents different dynamics compared to the neocortex
		21.1.4 Hippocampal cells are subjected to apoptosis during development
	21.2 GABAergic neurons and synapses develop prior to glutamatergic ones
		21.2.1 GABAergic interneurons divide and arborize prior to pyramidal neurons and granular cells
		21.2.2 GABAergic synapses are established before glutamatergic ones onto pyramidal cells
		21.2.3 Sequential expression of GABA and glutamate synapses is also observed in the hippocampus of subhuman primates in utero
		21.2.4 Questions about the sequential maturation of GABA and glutamate synapses
			21.2.4.1 These observations in turn raise the following questions
	21.3 GABA receptors-mediated responses differ in developing and mature brain neurons
		21.3.1 Activation of GABAA receptors is depolarizing and excitatory in immature networks because of a high intracellular concentra ...
			21.3.1.1 GABAA receptor activation evokes a depolarization and bursts of action potentials in immature hippocampal neurons
			21.3.1.2 GABAA receptor-mediated depolarization evokes Ca2+ entry through both the voltage-gated Ca2+ and NMDA channels
			21.3.1.3 There is a synergy between GABAA and NMDA receptor channels in the immature hippocampal neurons
			21.3.1.4 The developmental curve of [Cl−]i is exponential
			21.3.1.5 The developmental curve of [Cl−]i is interrupted around delivery
		21.3.2 GABAA receptor-mediated excitation is also observed in human embryonic cortex in vitro
		21.3.3 GABAA receptor-mediated excitation is also observed in rodent pups in vivo
		21.3.4 GABAB receptor-mediated IPSCs have a delayed expression in immature neurons
	21.4 Maturation of coherent network activities
		21.4.1 Network-driven giant depolarizing potentials provide most of the synaptic activity in the neonatal hippocampus
		21.4.2 Giant depolarizing potentials result from GABAergic and glutamatergic synaptic activity
		21.4.3 Giant depolarizing potentials are generated in the septal pole of the immature hippocampus and then propagate to the entire ...
		21.4.4 Hypotheses on the role of the sequential expression of GABA- and glutamate-mediated currents and of giant depolarizing pote ...
		21.4.5 Nonsynaptic intrinsic currents precede the expression of GDPs
	21.5 Concluding remarks
	Further reading
22. Chapter techniques
	22.1 Identification and localization of neurotransmitters and their receptors (Monique Esclapez)
		22.1.1 Immunohis(cy)tochemistry
			22.1.1.1 Principle and definitions
			22.1.1.2 Applications: Localization of neurons synthesizing a specific neurotransmitter
			22.1.1.3 Detection of the antigen–antibody complex
		22.1.2 In situ hybridization
			22.1.2.1 Principle
			22.1.2.2 Application
			22.1.2.3 Probes
			22.1.2.4 Markers
			22.1.2.5 Detection of the hybrids
		22.1.3 RNAscope in situ hybridization
		22.1.4 Freeze fracture electron microscopy
	22.2 Patch clamp recording techniques (Constance Hammond)
		22.2.1 General principles
			22.2.1.1 The patch clamp amplifier
			22.2.1.2 The recording electrode
			22.2.1.3 The various patch configurations
		22.2.2 How to record and drive membrane potential?
			22.2.2.1 Examples taken from the chapters
			22.2.2.2 How to record membrane potential? The whole-cell configuration and current clamp mode
			22.2.2.3 How to depolarize or hyperpolarize membrane potential? The injection of a current through the patch pipette
		22.2.3 How to record a total (I) or a unitary (i) current at a specific membrane potential (VH)?
			22.2.3.1 Examples taken from the book chapters
			22.2.3.2 How to record a total current I? The whole-cell configuration and voltage clamp mode
			22.2.3.3 How to record a unitary (single channel) current (i)?
			22.2.3.4 How to record a tail current?
	22.3 How to depolarize or hyperpolarize the recorded membrane?
		22.3.1 The injection of a current via the recording electrode
		22.3.2 The local or bath application of drugs (openers of ionic channels or agonists of receptor-channels)
			22.3.2.1 Depolarization of the recorded membrane
			22.3.2.2 Hyperpolarization of the recorded membrane
		22.3.3 Stimulation of a presynaptic neuron (pair recordings)?
	22.4 Optogenetic or chemogenetic excitation or inhibition of tagged neurons in a network (Clement Menuet and Andrew Allen)
		22.4.1 Optogenetics
		22.4.2 Putting optogenetics into practice (example of an in vivo experiment)
		22.4.3 Chemogenetics
		22.4.4 Putting chemogenetics into practice (example of in vivo experiments)
	22.5 Imaging intracellular calcium changes (François Michel)
		22.5.1 [Ca2+]i imaging techniques to record [Ca2+]i oscillations in vitro
			22.5.1.1 Examples of recordings taken from the book chapters
			22.5.1.2 Organic indicators for Ca2+
		22.5.2 [Ca2+]i imaging techniques to record [Ca2+]i oscillations in a specific neuronal population, in vitro or in vivo
			22.5.2.1 Genetically encoded calcium ion indicators
		22.5.3 Fluorescence measurements: general points
			22.5.3.1 Observation of fluorescence emission
		22.5.4 Confocal and multiphoton microscopy
	Further reading
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
	Z