Cellular and Molecular Neurobiology

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ISBN: 9780123116253 | 0123116252
Cover: Hardcover
Copyright: 5/1/2001

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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.

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

(4)

The somatodendritic tree is the neuron's receptive pole

(2)

The axon and its collaterals are the neuron's transmitter pole

(2)

Neurons are highly polarized cells with a differential distribution of organelles and proteins

(4)

The soma is the main site of macromolecule synthesis

(2)

The dendrites contain free ribosomes and synthesize some of their proteins

(2)

The axon, to a large extent, lacks the machinery for protein synthesis

(1)

Axonal transport allows bidirectional communication between the cell body and the axon terminals

(6)

Demonstration of axonal transport

(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

(3)

Retrograde axonal transport is responsible for the movement of membranous organelles back from axon terminals to the cell body

(1)

Slow anterograde axonal transport moves cytoskeletal proteins and cytosoluble proteins

(1)

Axonal transport of mitochondria allows the turnover of mitochondria in axons and axon terminals

(1)

Neurons connected by synapses form networks or circuits

(1)

The circuit of the withdrawal medullary reflex

(1)

The spinothalamic tract or anterolateral pathway is a somatosensory pathway

(1)

Summary: the neuron is an excitable and secretory cell presenting an extreme functional regionalization

(6)

Appendix 1.1 The cytoskeletal elements in neurons

(1)

Further reading

(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

(2)

Astrocytes are star-shaped cells characterized by the presence of glial filaments in their cytoplasm

(1)

Astrocytes maintain the blood brain barrier in the adult brain

(1)

Astrocytes regulate the ionic composition of the extracellular fluid

(1)

Astrocytes take part in the neurotransmitter cycle

(1)

Oligodendrocytes form the myelin shealths of axons in the central nervous system and allow the clustering of Na+ channels at nodes of Ranvier

(4)

Processes of interfascicular oligodendrocytes electrically isolate segments of central axons by forming the lipid-rich myelin sheath

(2)

Myelination enables rapid conduction of action potentials for two reasons

(1)

Microglia: ramified microglial cells represent the quiescent form of microglial cells in the central nervous system; they transform upon injury

(1)

Ramified microglial cells have long meandering processes

(1)

Do adult microglial cells play a role in immune processes?

(1)

Ependymal cells constitute an active barrier between blood and cerebrospinal fluid

(2)

Ependymal cells form an epithelium at the surface of the ventricles

(1)

Ependymal cells of the choroid plexus

(1)

Extrachoroidal ependymal cells

(1)

Schwann cells are the glial cells of the peripheral nervous system; they form the myelin sheath of axons or encapsulate neurons

(3)

Myelinating Schwann cells make the myelin sheath of peripheral axons

(1)

Non-myelinating Schwann cells encapsulate the axons and cell bodies of peripheral neurons

(1)

Further reading

(3)

Ionic Fluxes Across the neuronal Plasma Membrane

C. Hammond

Observation and questions

(3)

There is an unequal distribution of ions across neuronal plasma membrane

(1)

Neuronal plasma membrane is permeable to ions, allowing both passive and active transport of ions

(1)

There is a difference of potential between the two faces of the membrane, called membrane potential

(1)

Questions

(1)

Na+, K+, Ca2+ and Cl- ions passively cross the plasma membrane through transmembrane proteins - the channels

(8)

Channels are a particular class of transmembrane proteins

(1)

Voltage-gated channels open in response to a change in membrane potential

(1)

Ligand-gated channels opened by extracellular ligands, and receptor channels opened by neurotransmitters

(1)

Ligand-gated channels opened by intracellular ligands

(2)

Mechanically gated channels opened by mechanical stimuli

(1)

Other channels: junctional channels or gap junctions

(1)

Distribution of the various channels in the neuronal plasma membrane

(3)

The diffusion of ions through an open channel: What is an electrochemical gradient and an ionic current?

(5)

The structure of the channel pore determines the type of ion(s) that diffuse passively through the channel

(1)

The electrochemical gradient for a particular ion determines the direction of the passive diffusion of this ion through an open channel

(2)

The passive diffusion of ions through an open channel is a current

(2)

Active transport of Na+, K+, Ca2+, and Cl-ions by pumps and transporters maintain the unequal distribution of ions

(1)

Pumps are ATPases that actively transport ions

(1)

Transporters use the energy stored in the transmembrane electrochemical gradient of Na+ or other ions H+

(1)

Summary

(4)

Appendix 3.1 Hydrophobicity profile of a transmembrane protein

(1)

Appendix 3.2 The Nernst equation

(1)

Further reading

(1)

Basic Properties of Excitable Cells at Rest

A. Nistri

A. Gutman

Ionic channels open at rest determine the resting membrane potential

(4)

The plasma membrane separates two media of different ionic composition

(1)

At rest most of the channels open are K+ channels

(1)

In muscle cells, K+ and Cl- ion movements participate equally in resting membrane potential

(1)

In central neurons, K+, and Cl- and Na+ ion movements participate in resting membrane potential: the Goldman-Hodgkin-Katzs equation

(1)

Some principles related to the derivation of the GHK equation

(1)

Membrane pumps are responsible for keeping constant the concentration gradients across membranes

(1)

A simple equivalent electrical circuit for resting membrane properties

(3)

Membrane potential has an ohmic behaviour at rest

(2)

Stability, bistability and instability of resting membrane potential

(1)

An electrical model of resting membrane potential

(1)

Advantages and disadvantages of sharp (intracellular) versus patch electrodes for measuring the resting membrane potential

(2)

Background currents which flow through voltage-gated channels open at resting membrane potential also participate in Vrest

(2)

Further reading

(2)

The Voltage-Gated Channels of Na+ Action Potentials

(416)

C. Hammond

Properties of action potentials

(2)

The different types of action potentials

(1)

Na+ and K+ ions participate in the action potentials of axons

(2)

Na+-dependent action potentials are all or none and propagate along the axon with the same amplitude

(1)

Questions about the Na+-dependent action potential

(1)

The depolarization phase of Na+-dependent action potentials results from the transient entry of Na+ ions through voltage-gated Na+ channels

(16)

The Na+ channel consists of a principal large -subunit with four internal homologous repeats and auxiliary -subunits

(3)

Membrane depolarization favours conformational change of the Na+ channel towards the open state; the Na+ channel then quickly inactivates

(1)

The time during which the Na+ channel stays open varies around an average value, o, called the means open time

(2)

The iNa-V relation is linear: the Na+ channel has a constant unitary conductance Na

(1)

The probability of the Na+ channel being in the open state increases with depolarization to a maximal level

(3)

The macroscopic Na+ current (INa) has a steep voltage dependence of activation and inactivates within a few milliseconds

(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

(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

(1)

The repolarization phase of the sodium-dependent action potential results from Na+ channel inactivation and partly from K+ channel activation

(7)

The K+ channel consists of an -subunit with a single repeat and auxiliary -subunits

(1)

membrane depolarization favours the conformational change of the delayed rectifier channel towards the open state

(1)

The open probability of the delayed rectifier channel is stable during a depolarization in the range of seconds

(2)

The K+ channel has a constant unitary conductance K

(1)

The macroscopic delayed rectifier K+ current (IK) has a delayed voltage dependence of activation and inactivates within tens of seconds

(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

(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

(17)

Summary of the Na+-dependent action potential

(1)

Depolarization of the membrane to the threshold for voltage-gated Na+ channel activation has two origins

(1)

The site of initiation of Na+-dependent action potentials is the axon initial segment

(1)

The Na+-dependent action potential actively propagates along the axon to axon terminals

(1)

Do the Na+ and K+ concentrations change in the extracellular or intracellular media during firing?

(2)

The role of the Na+-dependent action potential is to evoke neurotransmitter release

(1)

Characteristics of the Na+-dependent action potential are explained by the properties of the voltage-gaged Na+ channel

(1)

Appendix Current clamp recording

(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

(1)

Mean open time of the GABAA channel

(1)

The GABAA receptor desensitizes

(1)

Pharmacology of the GABAA receptor

(1)

Bicululline and picrotoxin reversibly decrease total GABAA current; they are respectively competitive and non-competitive antagonists of the GABAA receptor

(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

(1)

GABAA-mediated synaptic transmission

(1)

The GABAergic synapse

(1)

The synaptic GABAA-mediated current is the sum of unitary currents appearing with variable delays and durations

(1)

The consequences of the synaptic activation of GABAA receptors depend on the relative values of ECl and Vm

(1)

What shapes the decay phase of GABAA-mediated currents?

(1)

Summary

(1)

Appendix 10.1 Mean open time and mean burst duration of the GABAA single-channel current

(1)

Further reading

(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

(1)

Ionotropic glutamate receptors have the name of their selective or preferential agaonist

(1)

The three ionotropic receptors participate in fast glutamatergic synaptic transmission

(1)

AMPA receptors are an ensemble of cationic receptor-channels with different permeabilities to Ca2+ ions

(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

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Cellular and Molecular Neurobiology

Summary

Table of Contents

Supplemental Materials