Cellular and Molecular Neurobiology

by Hammond

• ISBN13: 9780123116246
• ISBN10: 0123116244
• Edition: 2nd
• Format: Paperback
• Copyright: 2001-05-17
• Publisher: Elsevier Science & Technology

Summary

This Second Edition, is the new, thoroughly revised edition of the established and well-respected authoritative text in the field. Cellular and Molecular Neurobiology is hypothesis driven and firmly based on numerous experiments performed by experts in the field. Seven new chapters (five new and two totally rewritten) complement and expand on the first edition and are written in a way that encourages students to ask questions. Additionally, new, groundbreaking research data on dendritic processing is presented in a very easy-to-understand format.

Table of Contents

Contributors	xxii
Acknowledgements	xxiv
PART 1 Neurons: Excitable and Secretory Cells that Establish Synapses
Neurons
C. Hammond
Neurons have a cell body from which emerge two types of processes: the dendrites and the axon	3	(4)
The somatodendritic tree is the neuron's receptive pole	3	(2)
The axon and its collaterals are the neuron's transmitter pole	5	(2)
Neurons are highly polarized cells with a differential distribution of organelles and proteins	7	(4)
The soma is the main site of macromolecule synthesis	7	(2)
The dendrites contain free ribosomes and synthesize some of their proteins	9	(2)
The axon, to a large extent, lacks the machinery for protein synthesis	11	(1)
Axonal transport allows bidirectional communication between the cell body and the axon terminals	11	(6)
Demonstration of axonal transport	11	(1)
Fast anterograde axonal transport is responsible for the movement of membraneous organelles from cell body towards axon terminals, and allows renewal of axonal proteins	12	(3)
Retrograde axonal transport is responsible for the movement of membranous organelles back from axon terminals to the cell body	15	(1)
Slow anterograde axonal transport moves cytoskeletal proteins and cytosoluble proteins	16	(1)
Axonal transport of mitochondria allows the turnover of mitochondria in axons and axon terminals	17	(1)
Neurons connected by synapses form networks or circuits	17	(1)
The circuit of the withdrawal medullary reflex	17	(1)
The spinothalamic tract or anterolateral pathway is a somatosensory pathway	18	(1)
Summary: the neuron is an excitable and secretory cell presenting an extreme functional regionalization	18	(6)
Appendix 1.1 The cytoskeletal elements in neurons	21	(1)
Further reading	22	(2)
Neuron--Glial Cell Cooperation
C. Hammond
Astrocytes form a vast cellular network or syncytium between neurons, blood vessels and the surface of the brain	24	(2)
Astrocytes are star-shaped cells characterized by the presence of glial filaments in their cytoplasm	24	(1)
Astrocytes maintain the blood brain barrier in the adult brain	25	(1)
Astrocytes regulate the ionic composition of the extracellular fluid	26	(1)
Astrocytes take part in the neurotransmitter cycle	26	(1)
Oligodendrocytes form the myelin shealths of axons in the central nervous system and allow the clustering of Na+ channels at nodes of Ranvier	26	(4)
Processes of interfascicular oligodendrocytes electrically isolate segments of central axons by forming the lipid-rich myelin sheath	27	(2)
Myelination enables rapid conduction of action potentials for two reasons	29	(1)
Microglia: ramified microglial cells represent the quiescent form of microglial cells in the central nervous system; they transform upon injury	30	(1)
Ramified microglial cells have long meandering processes	30	(1)
Do adult microglial cells play a role in immune processes?	31	(1)
Ependymal cells constitute an active barrier between blood and cerebrospinal fluid	31	(2)
Ependymal cells form an epithelium at the surface of the ventricles	31	(1)
Ependymal cells of the choroid plexus	31	(1)
Extrachoroidal ependymal cells	32	(1)
Schwann cells are the glial cells of the peripheral nervous system; they form the myelin sheath of axons or encapsulate neurons	33	(3)
Myelinating Schwann cells make the myelin sheath of peripheral axons	33	(1)
Non-myelinating Schwann cells encapsulate the axons and cell bodies of peripheral neurons	33	(1)
Further reading	33	(3)
Ionic Fluxes Across the neuronal Plasma Membrane
C. Hammond
Observation and questions	36	(3)
There is an unequal distribution of ions across neuronal plasma membrane	36	(1)
Neuronal plasma membrane is permeable to ions, allowing both passive and active transport of ions	37	(1)
There is a difference of potential between the two faces of the membrane, called membrane potential	37	(1)
Questions	38	(1)
Na+, K+, Ca2+ and Cl- ions passively cross the plasma membrane through transmembrane proteins - the channels	39	(8)
Channels are a particular class of transmembrane proteins	39	(1)
Voltage-gated channels open in response to a change in membrane potential	40	(1)
Ligand-gated channels opened by extracellular ligands, and receptor channels opened by neurotransmitters	41	(1)
Ligand-gated channels opened by intracellular ligands	41	(2)
Mechanically gated channels opened by mechanical stimuli	43	(1)
Other channels: junctional channels or gap junctions	43	(1)
Distribution of the various channels in the neuronal plasma membrane	44	(3)
The diffusion of ions through an open channel: What is an electrochemical gradient and an ionic current?	47	(5)
The structure of the channel pore determines the type of ion(s) that diffuse passively through the channel	47	(1)
The electrochemical gradient for a particular ion determines the direction of the passive diffusion of this ion through an open channel	48	(2)
The passive diffusion of ions through an open channel is a current	50	(2)
Active transport of Na+, K+, Ca2+, and Cl-ions by pumps and transporters maintain the unequal distribution of ions	52	(1)
Pumps are ATPases that actively transport ions	52	(1)
Transporters use the energy stored in the transmembrane electrochemical gradient of Na+ or other ions H+	52	(1)
Summary	53	(4)
Appendix 3.1 Hydrophobicity profile of a transmembrane protein	54	(1)
Appendix 3.2 The Nernst equation	55	(1)
Further reading	56	(1)
Basic Properties of Excitable Cells at Rest
A. Nistri
A. Gutman
Ionic channels open at rest determine the resting membrane potential	57	(4)
The plasma membrane separates two media of different ionic composition	58	(1)
At rest most of the channels open are K+ channels	58	(1)
In muscle cells, K+ and Cl- ion movements participate equally in resting membrane potential	59	(1)
In central neurons, K+, and Cl- and Na+ ion movements participate in resting membrane potential: the Goldman-Hodgkin-Katzs equation	60	(1)
Some principles related to the derivation of the GHK equation	61	(1)
Membrane pumps are responsible for keeping constant the concentration gradients across membranes	61	(1)
A simple equivalent electrical circuit for resting membrane properties	62	(3)
Membrane potential has an ohmic behaviour at rest	62	(2)
Stability, bistability and instability of resting membrane potential	64	(1)
An electrical model of resting membrane potential	64	(1)
Advantages and disadvantages of sharp (intracellular) versus patch electrodes for measuring the resting membrane potential	65	(2)
Background currents which flow through voltage-gated channels open at resting membrane potential also participate in Vrest	67	(2)
Further reading	67	(2)
The Voltage-Gated Channels of Na+ Action Potentials	69	(416)
C. Hammond
Properties of action potentials	69	(2)
The different types of action potentials	69	(1)
Na+ and K+ ions participate in the action potentials of axons	69	(2)
Na+-dependent action potentials are all or none and propagate along the axon with the same amplitude	71	(1)
Questions about the Na+-dependent action potential	71	(1)
The depolarization phase of Na+-dependent action potentials results from the transient entry of Na+ ions through voltage-gated Na+ channels	71	(16)
The Na+ channel consists of a principal large -subunit with four internal homologous repeats and auxiliary -subunits	71	(3)
Membrane depolarization favours conformational change of the Na+ channel towards the open state; the Na+ channel then quickly inactivates	74	(1)
The time during which the Na+ channel stays open varies around an average value, o, called the means open time	75	(2)
The iNa-V relation is linear: the Na+ channel has a constant unitary conductance Na	77	(1)
The probability of the Na+ channel being in the open state increases with depolarization to a maximal level	77	(3)
The macroscopic Na+ current (INa) has a steep voltage dependence of activation and inactivates within a few milliseconds	80	(3)
Segment S4, the region between segments S5 and S6, and the region between domains III and IV play a significant role in activation, ion permetion and inactivation, respectively	83	(4)
Conclusion: the consequence of the opening of a population of N Na+ channels is a transient entry of Na+ ions which depolarizes the membrane above 0 mV	87	(1)
The repolarization phase of the sodium-dependent action potential results from Na+ channel inactivation and partly from K+ channel activation	87	(7)
The K+ channel consists of an -subunit with a single repeat and auxiliary -subunits	87	(1)
membrane depolarization favours the conformational change of the delayed rectifier channel towards the open state	88	(1)
The open probability of the delayed rectifier channel is stable during a depolarization in the range of seconds	89	(2)
The K+ channel has a constant unitary conductance K	91	(1)
The macroscopic delayed rectifier K+ current (IK) has a delayed voltage dependence of activation and inactivates within tens of seconds	92	(1)
Conclusion: during an action potential the consequence of the delayed opening of K+ channels is an exit of K+ ions which repolarizes the membrane to resting potential	93	(1)
Sodium-dependent action potential are initiated at the axon initial segment in response to a membrane depolarization and then actively propagate along the axon	94	(17)
Summary of the Na+-dependent action potential	95	(1)
Depolarization of the membrane to the threshold for voltage-gated Na+ channel activation has two origins	95	(1)
The site of initiation of Na+-dependent action potentials is the axon initial segment	96	(1)
The Na+-dependent action potential actively propagates along the axon to axon terminals	97	(1)
Do the Na+ and K+ concentrations change in the extracellular or intracellular media during firing?	97	(2)
The role of the Na+-dependent action potential is to evoke neurotransmitter release	99	(1)
Characteristics of the Na+-dependent action potential are explained by the properties of the voltage-gaged Na+ channel	99	(1)
Appendix Current clamp recording	99	(2)
Appendix Voltage clamp recording	101	(1)
Appendix Patch clamp recording	102	(1)
The various patch clamp recording configurations	103	(2)
Principles of the patch clamp recording technique	105	(2)
The unitary current i is a rectangular step of current	107	(1)
Determination of the conductance of a channel	107	(1)
Mean open time of a channel	108	(1)
Further reading	109	(2)
The Voltage-Gated Channels of Ca2+ Action Potentials: Generalization
C. Hammond
Properties of Ca2+-dependent action potentials	111	(1)
Ca2+ and K+ ions participate in the action potential of endocrine cells	111	(1)
Questions about the Ca2+- dependent action potential	111	(1)
The depolarizing or plateau phase of Ca2+-dependent action potentials results from the transient entry of Ca2+ ions through voltage-gated Ca2+ channels	112	(11)
The voltage-gated Ca2+ channels are a diverse group of multisubunit proteins	113	(2)
The L, N and P-type Ca2+ channels open at membrane potentials positive to -20 m V; they are high-threshold Ca2+ channels	115	(3)
Macroscopic L, N and P-type Ca2+ currents activate at a high threshold and inactivate with different time courses	118	(5)
The repolarization phase of Ca2+-dependent action potentials results from the activation of K+ current IK and Ik(Ca)	123	(5)
The Ca2+-activated K+ currents are classified as big K (BK) channels and small K (SK) channels	124	(2)
Ca2+ entering during the depolarization or the plateau phase of Ca2+-dependent action potentials activates K(Ca) channels	126	(2)
Calcium-dependent action potentials are initiated in axon terminals or in dendrites	128	(3)
Depolarization of the membrane to the threshold for the activation of L-, N- and P-type Ca+ channels has two origins	128	(2)
The role of the calcium-dependent action potentials is to provide a local and transient increase of [Ca2+], to trigger secretion, contraction and other Ca2+-gated processes	130	(1)
A note on voltage-gated channels and action potentials	131	(11)
Fluorescence measurements of intracellular Ca2+ concentration	131	(1)
The interaction of light with matter	131	(2)
The return from the excited state	133	(1)
Fluorescence measurements: general points	134	(1)
Fluorescence imaging hardware	135	(1)
Methods of calcium measurement by fluorescence	135	(2)
Two-photon absorption	137	(1)
Measurement of other ions by fluorescence techniques	138	(1)
Appendix Tail currents	139	(1)
Further reading	140	(2)
The Chemical Synapses
C. Hammond
The synaptic complex's three components: presynaptic element, synaptic cleft and postsynaptic element	142	(7)
The pre- and postsynaptic elements are morphologically and functionally specialized	142	(2)
General functional model of the synaptic complex	144	(2)
Complementarity between the neurotransmitter stored and released by the presynaptic element and the nature of receptors in the postsynaptic membrane	146	(3)
The interneuronal synapses	149	(3)
In the CNS the most common synapses are those where an axon terminal is the presynaptic element	149	(1)
At low magnification, the axo-dendritic synaptic contacts display features implying various functions	149	(1)
Interneuronal synapses display ultrastructural characteristics that vary between two extremes: types 1 and 2	150	(2)
The neuromuscular junction is the group of synaptic contacts between the terminal arborization of a motor axon and a striated muscle fibre	152	(4)
In the axon terminals, the synaptic vesicles are concentrated at the level of the electrondense bars; they contain acetylcholine	153	(1)
The synaptic cleft is narrow and occupied by a basal lamina which contains acetylcholinesterase	153	(2)
Nicotinic receptors for acetylcholine are abundant in the crests of the folds in the postsynaptic membrane	155	(1)
Mechanisms involved in the accumulation of postsynaptic receptors in the folds of the postsynaptic muscular membrane	155	(1)
The synapse between the vegetative postganglionic neuron and the smooth muscle cell	156	(3)
The presynaptic element is a varicosity of the postganglionic axon	156	(2)
The width of the synaptic cleft is very variable	158	(1)
The autonomous postaganglionic synapse is specialized to ensure a widespread effect of the neurotransmitter	158	(1)
Example of a neuroglandular synapse	159	(1)
Summary	160	(9)
Appendix Neurotransmitters, agonists and antagonists	160	(1)
Criteria to be satisfied before a molecule can be identified as a neurotransmitter	161	(1)
Types of neurotransmitter	161	(1)
Agonists and antagonists of a receptor	162	(1)
Identification and localization of neurotransmitters and their receptors	162	(4)
M. Esclapez
Immunocytochemistry	166	(1)
In situ hybridization	166	(1)
Further reading	167	(2)
Neurotransmitter Release
C. Hammond
Observations and questions	169	(5)
Quantitaive data on synapse morphology and synaptic transmission	169	(2)
Ways of estimating neurotransmitter release in central mammalian synapses	171	(3)
Questions	174	(1)
Presynaptic processes I: From presynaptic spike to [Ca2a+], increase	174	(6)
The presynaptic Na+-dependent spike depolarizes the presynaptic emembrane, opens presynaptic Ca2+ channels and triggers Ca2+ entry	174	(1)
Ca2+ enters the presynaptic bouton during the time course of the presynaptic spike through high-voltage-activated Ca2+channels (N- and P/Q-types)	174	(1)
Presynaptic [Ca2+]i increase is transient and restricted to micro- or nanodomains close to docked vesicles	175	(4)
Ca2+ clearance makes presynaptic [Ca2+]i increase transient: it shapes its amplitude and duraction	179	(1)
Presynaptic processes II: From [Ca2+]i increase to synaptic vesicle fusion	180	(8)
Overview of the hypothetical vesicle cycle in presynaptic terminals	180	(2)
Docking: a subpopulation of synpatic vesicles is docked to the active zone close to Ca2+ channels by means of specific pairing of vesicular and plasma membrane proteins	182	(3)
Three to four Ca2+ ions must bind to Ca2+ receptors(s) to initiate vesicle fusion (exocytosis)	185	(1)
Fusion: from Ca2+ binding to exocytosis	186	(1)
Pharmacology of neurotransmitter release	187	(1)
Proceses in the synaptic cleft: from transmitter release in the cleft to transmitter clearance from the cleft	188	(3)
The amount of neurotransmitter released in the synaptic cleft	188	(2)
Transmitter time course in the synaptic cleft is brief and depends mainly on transmitter binding to target proteins	190	(1)
Summary	191	(11)
Appendix 8.1 Quantal nature of neurotransmitter release	193	(1)
Spontaneous release of acetylcholine at the neuromuscular junction evokes miniature endplate potentials: the notion of quanta	193	(1)
The quantal composition of EPSPs and IPSPs	194	(1)
Appendix 8.2 The probabilistic nature of neurotransmitter release	194	(1)
The neuromuscular junction as a model	194	(2)
Inhibitory synapses between interneurons and the Mauthner cell in the teleost fish bulb, as a model	196	(2)
Further reading	198	(4)
PART 2 Ionotropic and Metabotropic Receptors in Synaptic Transmission and Sensory Transduction
The Ionotropic Nicotinic Acetylcholine Receptors
C. Hammond
Observations
The torpedo or muscle nicotinic receptor of acetylcholine is a heterologous pentamer α2βγδ	202	(5)
Nicotinic receptors have a rosette shape with an aqueous pore in the centre	203	(1)
The four subunits of the nicotinic receptor are assembled as a pentamer α2βγδ	203	(2)
Each subunit presents two main hydrophilic domains and four hydrophobic domains	205	(1)
Each α-subunit contains one acetylcholine receptor site located in the hydrophilic NH2 terminal domain	206	(1)
The pore of the ion channel is lined by the M2 transmembrane segments of each of the five subunits	207	(1)
Binding of two acetylcholine molecules favours conformational change of the protein towards the open state of the cationic channel	207	(7)
Demonstration of the binding of two acetylcholine molecules	207	(1)
The nicotinic channel has a selective premeability to cations: its unitary conductance is constant	208	(4)
The time during which the channel stays open varies around an average value o, the mean open time, and is a characteristic of each nicotnic receptor	212	(2)
The nicotinic receptor desensitizes	214	(3)
nAChR-mediated synaptic transmission at the neuromuscular junction	217	(3)
Miniature and endplate synaptic currents are recorded at the neuromuscular junction	217	(2)
Synaptic currents are the sum of unitary currents appearing with variable delays and durations	219	(1)
Nicotinic transmission pharmacology	220	(3)
Nicotinic agonists	220	(1)
Competitive nicotinic antagonists	220	(1)
Channel blockers	221	(1)
Acetylcholinesterase inhibitors	222	(1)
Summary	223	(4)
Appendix 9.1 The neuronal nicotnic receptors	223	(2)
Further reading	225	(2)
The Ionotropic GABAA Receptor
C. Hammond
Observations and questions	227	(1)
GABAA receptors are hetero-oligomeric proteins with a structural heterogeneity	227	(3)
The diversity of GABAA receptor subunits	227	(1)
Subunit composition of native GABAA receptors and their binding characteristics	228	(2)
Binding of two GABA molecules leads to a conformational change of the GABAA receptor into an open state; the GABAA receptor desensitizes	230	(207)
GABA binding site	230	(1)
Evidence for the binding of two GABA molecules	230	(1)
The GABAA channel is selectively permeable to Cl-ions	230	(207)
The single-channel conductance of GABAA channels is constant is symmetrical Cl-solution, but varies as a function of potential in asymmetrical solutions	23	(1)
Mean open time of the GABAA channel	23	(1)
The GABAA receptor desensitizes	23	(1)
Pharmacology of the GABAA receptor	23	(1)
Bicululline and picrotoxin reversibly decrease total GABAA current; they are respectively competitive and non-competitive antagonists of the GABAA receptor	23	(215)
Benzodiazepines, barbiturates and neurosteroids reversibly potentiate total GABAA current; they are allosteric agonists at the GABAA receptor	238	(214)
β-carbolines reversibly decrease total GABAA current; they bind at the benzodiazepine site and are inverse agonists of the GABAA receptor	24	(1)
GABAA-mediated synaptic transmission	24	(1)
The GABAergic synapse	24	(1)
The synaptic GABAA-mediated current is the sum of unitary currents appearing with variable delays and durations	24	(1)
The consequences of the synaptic activation of GABAA receptors depend on the relative values of ECl and Vm	24	(1)
What shapes the decay phase of GABAA-mediated currents?	24	(1)
Summary	24	(1)
Appendix 10.1 Mean open time and mean burst duration of the GABAA single-channel current	24	(1)
Further reading	25	(1)
The Ionotropic Glutamate Receptors
C. Hammond
The three different types of ionotropic glutamate receptors have a common structure and participate in fast glutamatergic synaptic transmission	25	(1)
Ionotropic glutamate receptors have the name of their selective or preferential agaonist	25	(1)
The three ionotropic receptors participate in fast glutamatergic synaptic transmission	25	(1)
AMPA receptors are an ensemble of cationic receptor-channels with different permeabilities to Ca2+ ions	25	(232)
The diversity of AMPA receptors results from subunit combination, alternative splicing and post-transcriptional nuclear editing	253	(1)
The native AMPA receptor is permeable to cations and has a unitary conductance of 8 pS	254	(3)
AMPA receptors are permeable to Na+, K+ and Ca2+ ions unless the edited from of GluR23 is present; in the latter case, AMPA receptors are impermeable to Ca2+ ions	257	(1)
The presence of flip or flop isoforms plays a role on the amplitude of the total AMPA current	257	(1)
Kainate receptors are an ensemble of cationic receptor channels with different permeabilities to Ca2+ ions	257	(2)
The diversity of kainate receptors	257	(1)
Native kainate receptors are permeable to cations	258	(1)
NMDA receptors are cationic receptor-channels highly permeable to Ca2+ ions; they are blocked by Mg2+ ions at voltages close to the resting potential, which confers strong voltage-dependence	259	(8)
Molecular biology of NMDA receptors	259	(2)
Native NMDA receptors have a high unitary conductance of 40-50 pS	261	(1)
The NMDA channel is highly permeable to monovalent cations and to Ca2+	261	(1)
NMDA channels are blocked by physiological concentrations of extracellular Mg2+ ions; this block is voltage - dependent	262	(3)
Glycine is a co-agonist of NMDA receptors	265	(1)
Conclusions on NMDA recepors	265	(2)
Synaptic responses to glutamate are mediated by NMDA and non-NMDA receptors	267	(5)
Glutamate receptors are co-localized in the postsynaptic membrane of glutamatergic synapses	267	(1)
The glutamatergic postsynaptic current is inward and can have at least two components in the absence of extracellular Mg2+ ions	268	(2)
The glutamatergice postsynaptic depolarization (EPSP) has at least two components in the absence of extracellular Mg2+ ions	270	(1)
Synaptic depolarization recorded in physiological conditions: factors controlling NMDA receptors activation	270	(2)
Summary	272	(2)
Further reading	272	(2)
Ionotropic Mechanoreceptors: the Mechanosensitive Channels
C. Bourque
Mechanoreception in sensory neurons is associated with the production of a receptor potential	274	(1)
Discovery of mechanosensitive ion channels provided a potential molecular mechanism for mechanotransduction	274	(1)
Structural basis for the mechanical gating of ion channels	275	(1)
Intrinsic and extrinsic forms of mechanical gating	275	(1)
Channels regulated by coupling molecules oriented orthogonally to the membrane	275	(1)
Channels regulated by coupling molecules parallel to the membrane	275	(1)
Other Gating Configurations	276	(1)
Classification of stretch-sensitive ion channels	276	(2)
Patch clamp experiments reveal the existence of stretch-activated and stretch-inactivated channels	276	(1)
Ionic permeability of stretch-sensitive channels	277	(1)
Mechanosensitive ion channels and mechanotransduction	278	(1)
Osmoreceptors in the central nervous system	278	(3)
Electrical activity and neuro pophyseal hormone secretion	279	(1)
Magnocellular neurosecretory cells in the hypothalamus are intrinisc osmoreceptors	280	(1)
Osmoreception in magnocellular neurosecretory cells	281	(3)
Osmoreceptor potentials reflect the modulation of a non-selective cationic conductance	281	(1)
Changes in cell volume directly regulate the macroscopic cationic conductance in magnocellular neurosecretory cells	281	(1)
Magnocellular neurosecretory cells express stretch-inactivated cationic channels	282	(1)
The in hibtiory effects of Gd3+ provide pharmacological evidence for the involvement of the stretch-inactivated cation channels in osmoreception	283	(1)
Molecular basis for mechanotransducation in osmoreceptors	283	(1)
Conclusions	284	(3)
Further reading	286	(1)
The Metabotropic GABAB Receptors
D. Mott
GABAB receptors were originally discovered because of their insensitivity to bicuculline and their sensitivity to baclofen	287	(1)
Structure of the GABAB receptor	288	(4)
GABAB receptors belong the family-3G-protein coupled receptors	288	(3)
GABAB receptors are heterodimers	291	(1)
GABAB receptors are located throughout the brain at both presynaptic and postsynaptic sites	292	(1)
Summary	292	(1)
GABAB receptors are G-protein-coupled to a variety of different effector mechanisms	292	(16)
GABAB receptors are coupled to inhibitory G proteins	293	(1)
GABAB receptors regulate the activity of adenylyl cyclase	294	(2)
GABAB receptors activation inhibits voltage-dependent calcium channels	296	(6)
GABAB receptors activate potassium channels	302	(6)
Summary	308	(1)
The functional role of GABAB receptors in synaptic activity	308	(4)
Postsynaptic GABAB receptors produce an inhibitory postsynaptic current	309	(1)
Presynaptic GABAB receptors inhibit the release of many different transmitters	310	(2)
Summary	312	(2)
Further reading	313	(1)
The Metabotropic Glutamate Receptors
G. Bhave
R. Gereau
What is the receptor underlying glutamate-stimulated PI hydrolysis? - The cloning of metabotropic glutamate receptor genes	314	(1)
How do metabotropic glutamate receptors carry out their function? - Structure - function studies of metabotropic glutamate receptors	315	(2)
What biochemical means do metabotropic glutamate receptors utilize to elicit physiological changes in the nervous system? - Signal transduction studies of metabotropic glutamate receptors	317	(2)
What are the functions of metabotropic glutamate receptors in the nervous system? - Physiological and genetic studies of mGluRs	319	(4)
How are metabotropic glutamate receptors specifically localized in neurons to execute their functions? - Studies of MGluR postsynaptic localization	323	(1)
How is the acivity of metabotropic glutamate receptors modulated? - Studies of mGluR desensitization	324	(1)
Summary	325	(2)
Further reading	325	(2)
The Metabotropic Olfactory Receptors
C. Hammond
The olfactory receptor cells are sensory neurons located in the olfactory neuroepithelium	327	(2)
The olfactory neurons are bipolar cells that project to the olfactory bulb	327	(2)
Odorants diffuse through the extracellular mucous matrix before interacting with the chemosensory membrane of olfactory receptor neurons	329	(1)
The response of olfactory receptor neurons to odours is a membrane depolarization which elicits action potential generation	329	(1)
Odorants bind to a family of G-protein-linked receptors which activate adenylat cyclase	330	(2)
Odorant receptors are a family of G-protein-linked receptors	330	(2)
The activation of odorant receptors leads to the activation of inward current adenyltae cyclase and the rapid formation of cAMP via the activation of a Gs - like protein	332	(1)
cAMP opens a cycle nucleotide-gated channel and generates an inward current	332	(11)
The olfactory cyclic nucleotide - gated channels is a ligand channel composed of ieast two different subunits	332	(1)
cAMP directly opens a cyclic nucleotide-grated channel	333	(5)
The activation of N cyclic nucleotide - gated channels envokes an inwrd depolarizing current by cations	338	(4)
The cyclic nucleotide-gated conductance and the odour-gated conductance are identical	342	(1)
Conclusions	342	(1)
The odorant-evoked inward current evokes a membrane depolarization that spreads electronically to the axon hillock where it can elicit action potentials	343	(2)
The odorant-induced inward current depolarizes the membrane of olfactory receptors: the generator potential	343	(1)
The odorant-induced depolarization takes place in the cilia; spikes are initiated in the soma-initial axon segment, and the pattern of spike discharge propagated codes for the concentration and duration of the odorant stimulus	344	(1)
The nature of the odorant would be coded by the nature of the olfactory neuron stimulated and the synaptic arrangements in the olfactory bulb	344	(1)
Conclusions	345	(5)
Further reading	345	(5)
PART 3 Somato-Dendritic Processing and Plasticity of Postsynaptic Potentials
Somato-Dendritic Processing of Postsynaptic Potentials. I: Passive Properties of Dendrites
C. Hammond
Propagation of excitatory and inhibitory postsynaptic potentials through the dendritic arborization	350	(1)
The complexity of synaptic organization (Figure 16.1)	350	(1)
Passive decremental propagation of postsynaptic potentials	351	(1)
Passive and non-decremental propagation of postsynaptic potentials	351	(1)
Summation of excitatory and inhibitory postsynaptic potentials	351	(3)
Linear and nonlinear summation of excitatory postsynaptic potentials	351	(3)
Linear and nonlinear summation of inhibitory postsynaptic potentials	354	(1)
The integration of excitatory and inhibitory postsynaptic potentials partly determines the configuration of the postynaptic discharge	354	(1)
Summary	354	(5)
Further reading	355	(4)
Subliminal Voltage-Gated Currents of the Somato-Dendritic Membrane
C. Hammond
Observations and questions	359	(1)
The subliminal voltage-gated currents that depolarize the membrane	359	(8)
The persistent inward Na+ current, INaP	359	(2)
The low-threshold transient Ca2+ current, ICaT	361	(3)
The hyperpolarization-activated cationic current, Ih, If, Iq	364	(3)
The subliminal voltage-gated currents that hyperpolarize the membrane	367	(5)
The rapidly inactivating transient K+ current: IA or IAf	367	(1)
The slowly inactivating transient K+ current, ID or IAs	368	(1)
The K+ currents activated by intracellular Ca2+ ions, IKCa	369	(1)
The K+ current sensitive to muscarine, IM	369	(2)
The inward rectifier K+ current, IKir	371	(1)
Conclusions	372	(3)
Further reading	372	(3)
Somato-Dendritic Processing of Postsynaptic Potentials. II. Role of Subliminal Depolarizing Voltage-Gated Currents
C. Hammond
Persistent Na+ channels are present in soma and dendrites of neocortical neurons; INaP boosts EPSPs in amplitude and duration	375	(3)
Persistent Na+ channels are present in the dendrites and soma of pyramidal neurons of the neocortex	375	(1)
Dendritic persistent Na+ channels are activated by EPSPs; in turn, INaP boosts EPSP amplitude	376	(2)
T-type Ca2+ channels are present in dendrites of neocortical neurons; ICaT boosts EPSPs in amplitude and duration	378	(4)
T-type Ca2+ channels are present in dendrities of pyramidal neurons of the hippocampus	378	(1)
Dendritic T-type Ca2+ channels are activated by EPSPs; in turn, ICaT boosts EPSPs amplitude	378	(4)
The hyperpolarization-activated cationic current Ih is present in dendrites of hippocampa pyramidal neurons; for EPSPs, dendritic Ih decreases the current transmitted from the dendrites to the soma	382	(4)
H-type cationic channels are expressed in dendrites of pyramidal neurons of the hippocampus	382	(1)
Dendritic H-type cationic channels are activated by IPSPs; in turn, Ih decreases EPSPs amplitude	383	(3)
Functional consequences	386	(1)
Amplification of distal EPSPs by INaP and ICaT counteracts their attenuation owing to passive propagation to the soma; it also favours temporal summation versus spatial summation	386	(1)
Activation of dendritic ICaT generates a local dendritic [Ca2+], transient	386	(1)
Activation of dendritic Ih, INaP and ICaT alter the local membrane resistence and time constant	386	(1)
Conclusions	386	(4)
Further reading	387	(3)
Somato-Dendritic Processing of Postsynaptic Potentials. III. Role of High-Voltage-Activated Depolarizing Currents
C. Hammond
High-voltage-activated Na+ and/or Ca2+ channels are present in the dendritic membrane of some CNS neurons, but are they distributed with comparable densities in soma and dendrites?	390	(8)
High-voltage-activated Na+ channels are present in some dendrites	390	(2)
Dendritic Na+ channels are opened by EPSPs and the resultant Na+ current boosts EPSPs in amplitude and duration	392	(2)
Dendritic Na+ channels are opened by backpropagating Na+ action potentials	394	(4)
High-voltage-activated Ca2+ channels are present in the dendritic membrane of some CNS neurons, but are they distributed with comparable densities in soma and dendrites?	398	(5)
High-voltage-activated Ca2+ channels are present in some dendrites	398	(2)
High-voltage-activated Ca2+ channels of Purkinje cell dendrites are opened by climbing fibre EPSP; this initiates Ca2+ action potentials in the dendritic tree of Purkinje cells	400	(3)
Dendritic high-voltage-activated Ca2+ channels are opened by backpropagating Na+ action potentials	403	(1)
Functional consequences	403	(2)
Amplification of distal synaptic responses by dendritic HVA currents counteracts their attenuation due to passive propagation to the soma	403	(1)
Active backpropagation of Na+ spikes in the dendritic tree depolarizes the dendritic membrane, with multiple consequences	404	(1)
Initiation of Ca2+ spikes in the dendritic tree of Purkinje cells evokes a widespread intradendritic [Ca2+] increase	405	(1)
Conclusions	405	(2)
Further reading	406	(1)
Firing Patterns of Neurons
C. Hammond
Medium spiny neurons of the neostriatum are silent neurons that respond with a long latency	407	(3)
Medium spiny neurons are silent at rest owing to the activation of an inward rectifier K+ current	407	(2)
When activated, the response of medium spiny neurons is a long-latency regular discharge	409	(1)
Inferior olivary cells are silent neurons that can oscillate	410	(4)
Inferior olivary cells are silent at rest in the absence of afferent activity	410	(1)
When depolarized, inferior olivary cells oscillate at a low frequency (3--6 Hz)	411	(2)
When hyperpolarized, inferior olivary cells oscillate at a higher frequency (9--12 Hz)	413	(1)
Purkinje cells are pacemaker neurons that respond by a complex spike followed by a period of silence	414	(3)
Purkinje cells present an intrinsic tonic firing that depends on a persistent Na+ current	414	(1)
Purkinje cells respond to climbing fibre activation by a complex spike	414	(3)
Thalamic and subthalamic neurons are pacemaker neurons with two intrinsic firing modes: a tonic and a bursting mode	417	(7)
The intrinsic tonic (single-spike) mode depends on a persistent Na+ current	419	(1)
The bursting mode depends on a cascade of subliminal inward currents: Ih, ICaT, ICaN	420	(1)
The transition from one mode to the other in response to synaptic inputs	420	(3)
Further reading	423	(1)
Synaptic Plasticity
C. Hammond
Short-term potentiation (STP) of a cholinergic synaptic response as an example of short-term plasticity: the cholinergic response of muscle cells to motoneuron stimulation	424	(1)
Long-term potentiation (LTP) of a glutamatergic synaptic response: example of the glutamatergic synaptic response of pyramidal neurons of the CA1 region of the hippocampus to Schaffer collaterals activation	425	(12)
The Schaffer collaterals are axon collaterals of CA3 pyramidal neurons which form glutamatergic excitatory synapses with dendrites of CA1 pyramidal neurons	425	(2)
Observation of the long-term potentiation of the Schaffer collateral-mediated EPSP	427	(1)
Long-term potentiation (LTP) of the glutamatergic EPSP recorded in CA1 pyramidal neurons results from an increase of synaptic efficacy (or synaptic strength)	427	(2)
Induction of LTP results from a transient enhancement of glutamate release and a rise in postsynaptic intracellular Ca2+ concentration	429	(5)
Expression of LTP (also called maintenance) involves a persistent enhancement of the AMPA component of the EPSP	434	(1)
Multiple ways to induce LTP, multiple forms of LTP and multiple ways to block LTP induction	435	(2)
Summary: principal features of LTP in the Schaffer collateral--pyramidal cell glutamatergic transmission	437	(1)
The long-term depression (LTD) of a glutamatergic response: example of the response of Purkinje cells of the cerebellum to parallel fibre stimulation	437	(14)
The long-term depression of a postsynaptic response (EPSC or EPSP) is a decrease of synaptic efficacy	437	(1)
Induction of LTD requires a rise in postsynaptic intracellular Ca2+ concentration and the activation of postsynaptic AMPA receptors	438	(5)
The expression of LTD involves a persistent desensitization of postsynaptic AMPA receptors	443	(1)
Second messengers are required for LTD induction: examples of protein kinases C and nitric oxide (NO)	443	(3)
The different ways to induce or block cerebellar LTD	446	(2)
Summary: Principal features of LTD in parallel-fibre/Purkinje-cell glutamatergic transmission	448	(1)
Further reading	448	(3)
PART 4 Activity and Development of Networks: The Hippocampus as an Example
The Adult Hippocampal Network
C. Hammond
Observations and questions	451	(2)
The hippocampal circuitry	453	(5)
Ammon's horn	453	(1)
The dentate gyrus	454	(3)
Principal cells form a tri-neural excitatory circuit	457	(1)
Extrinsic afferences to principal cells and interneurons	457	(1)
Activation of interneurons evoke inhibitory GABAergic responses in postsynaptic pyramidal cells	458	(6)
Experimental protocol to study pairs of neurons	458	(1)
Unitary inhibitory postsynaptic currents (IPSCs) evoked by different types of interneurons are all GABAA-mediated but have different kinetics when recorded at the level of the soma	458	(3)
GABAA-mediated IPSCs generate IPSPs in postsynaptic pyramidal cells	461	(3)
GABAB-mediated IPSPs are also recorded in pyramidal neurons in reponse to strong interneuron stimulation	464	(1)
Activation of principal cells evokes excitatory glutamatergic responses in postysynaptic interneurons and other principal cells (synchronization in CA3)	464	(2)
Pyramidal neurons evoke AMPA-mediated EPSPs in interneurons	465	(1)
EPSPs in interneurons lead to feedback inhibition of pyramidal neurons	466	(1)
CA3 pyramidal neurons are monosynaptically connected via glutamatergic synapses	466	(1)
Overview of intrinsic hippocampal circuits	466	(1)
Oscillations in the hippocampal network: example of sharp waves (SPW)	466	(4)
Summary	470	(2)
Further reading	471	(1)
Maturation of the Hippocampal Network
Y. Ben Ari
C. Hammond
GABAergic neurons and GABAergic synapses develop prior to glutamatergic ones	472	(4)
GABAergic interneurons divide and arborize prior to pyramidal neurons and granular cells	472	(1)
GABAergic synapses are the first synapses established on to pyramidal cells	473	(1)
Sequential expression of GABA and glutamate synapses is also observed in the hippocampus of subhuman primates in utero	474	(2)
Questions about the sequential maturation of GABA and glutamate synapses	476	(1)
GABAA-and GABAB-mediated responses differ in developing and mature brains	476	(4)
Activation of GABAA receptors is depolarizing and excitatory in immature networks because of a high intracellular concentration of chloride	476	(3)
GABAB-receptor-mediated IPSCs have a delayed expression in immature neurons	479	(1)
Network-driven giant depolarizing potentials (GDPs) provide most of the synaptic activity in the neonatal hippocampus	480	(3)
Giant depolarizing potentials result from GABAergic and glutamatergic synaptic activity	481	(1)
Giant depolarizing potentials are generated in the septal pole of the immature hippocampus and then propagate to the entire structure	482	(1)
Hypotheses on the role of the sequential expression of GABA- and glutamate-mediated currents and of giant depolarizing potentials	483	(1)
Conclusions	483	(2)
Further reading	484	(1)
Index	485