Introduction

Excitatory neurotransmission in the central nervous system is dominated by one transmitter: glutamate. Due to its now well-established role in many aspects of neuronal communication, plasticity and pathology, it has been the focus of intense research in many laboratories around the world. As a consequence, the amount of literature relevant to glutamate and neuronal function has reached a size that most researchers (especially those at the start of their career) will probably consider overwhelming.

Therefore, the present book chapter aims to give a concise overview of the current knowledge on glutamate receptors and learning and memory. Experimental details however, as well as the vast amount of data obtained by in vitro studies, are only referred to when necessary. To satisfy the more experienced reader, we also provide an extensive review of the literature in tabular form.

Glutamate receptors can be classified into two major classes: ionotropic receptors (iGlu) coupled to cation channels; and metabotropic receptors (mGlu), coupling to intracellular second messenger cascades. Within these two classes, specific receptor types and their subunits have been characterised using molecular, pharmacological, and physiological techniques (Table 1). These properties have been extensively reviewed elsewhere.58, 27,159, 72

Ionotropic receptors to be considered here comprise a-amino-3-hydroxy-5-methyl-

4-isoxazoleproprionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Kainate receptors only attracted interest more recently157 and very little is know on their behavioural role. AMPA receptors are the main source of fast excitatory transmission and as such a rather obvious but unspecific keyplayer in learning and memory formation. In contrast, NMDA

From Messengers to Molecules: Memories Are Made of These, edited by Gemot Riedel and Bettina Platt. ©2004 Eurekah.com and Kluwer Academic / Plenum Publishers.

Table 1. Glutamate receptor classification

Ionotropic Receptors

Metabotropic Receptors

NMDA

AMPA

Kainate*

Group I

Group II

Group III

Subunits/

NR1

GluR1-4

GluR5-7

1 (a-d),

2, 3

4 (a&b), 6,

Subtypes

NR2A-D

(also called

KA1&2

5 (a&b)

7 (a&b), 8

NR3A

GluRA-GluRD

Current/

Ca2+, Na+,

Na+, K+,

Na+, K+, (Ca2+)2

PLC f

AC i

AC i

Signalling

K+

(Ca2+)1

^ IP3 + DAG

^ cAMP i

^ cAMP i

Cascade

^ PKC f

^ Cai2+

Agonists

NMDA

Quinolinate

Kainate

Quisqualate

ACPD

AP4

Ibotenate

AMPA

Domoate

ACPD

DCG-IV

Quinolinate

Domoate

ATPA (R5)

DHPG

L-CCG-I

AMAA

Fluorowillar-diine

Iodowillardiine (R5)

CHPG (5)

4-CPG

ATPA

Acromelic acid

3-HPG

APDC

LY262466

(AMPA)

t-ADA

LY354740

(Kainate)

Antagonist

AP5, AP7

CNQX, NBQX,

CNQX, NBQX,

MCPG

MCPG

(MCPG)

MK-801

DNQX

DNQX

4-CPGv

MTPG

MPPG

PCP/TCP

JST

GAMS

MPEP (5)

LY341495

MAP4

Dextromethorphan

Barbiturates

AMOA

LY367385 (1)

MSOP

Ketamine

(e.g. GYKI 52466,

NS-102

CPCCOEt

Memantine

GYKI53655)

AIDA

Ifenprodil (NR2B)

GDEE

AP3

CGP37849

LY326325

CGP39551

LY215490

CGS19755

SYM 2206

LY233536

YM90K

Continued on next page

Continued on next page

Table 1. Continued

Modulators Positive:

7CI Kyn HA-966 Arcaine

Glycine, D-serine D-cycloserine Polyamines Negative: Zn2+, H+, Mg2+

NMDA

Anirazetam Cyclothiazide

AMPA

IDRA 21

CX516 1-BCP

Lectins, e.g. Concanvalin A (ConA)

Kainate*

Group I

Group II

Group III

This table gives an overview over the principle glutamate receptors and lists some of the pharmacological tools used in behavioral studies. *: kainate receptors have been included for completion despite the lack of behavioral data. Abbreviations: Drug names:

ACPD: 1 S,3R-1- aminocyclopentane dicarboxylate;

AIDA (=UPF 523): (RS)-1-aminoindan-1,5-dicarboxylic acid;

AMAA: 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid;

AMOA: 2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid;

AMPA: A-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid;

AP3: DL-2-amino-3-phosphonopropionic acid;

AP4: L(+)-2-amino-4-phosphonobutyric acid

AP5: D-2-amino-5-phosphonovaleric acid;

AP7: 2-amino-7-phosphonoheptanoic acid

APDC: (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid;

ATPA: DL-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid;

1-BCP: 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine;

L-CCG-1: (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine;

CGS 19755: cis-4-phosphonomethyl-2-piperadine carboxylic acid;

CHPG: (R,S)-2-chloro-5-hydroxyphenylglycine;

7Cl Kyn: 7-chlorokynurenic acid;

CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione;

4-CPG: (RS)--ethyl-4-carboxyphenylglycine;

CPP: cis(±)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid; CPCCOEt: 7-(Hydroxyimino)cyclopropa[b] chromen-1a-carboxylate ethyl ester;

Cyclothiazide: 6-chloro-3,4-dihydro-3-(2-norbornen-5-yl)-2H-1,2,4-benzothiadiazine-7-sulphonamide-1,1-dioxide;

Continued on next page

Table 1. Continued

CX516: 1-(quinoxalin-6-ylcarbonyl)-piperidine; DCG-IV: (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine; DHPG: (S)-3,5- dihydroxyphenylglycine; DNQX: 6,7-dinitroquinoxaline-2,3-dione;

Domoate: [2S-[2a,3b,4b(1Z,3E,5R)]]-2-Carboxy-4-(5-carboxy-1-methyl-1,3-hexadienyl)-3-pyrrolidineacetic acid; GAMS: y-D-glutamylaminomethyl sulphonic acid; GDEE: L-glutamicacid-diethylesther;

GYKI 52466: 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine;

GYKI53655 (= LY300168; LY303070: the active isomer of GYKI53655): 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-(3N-methylcarbamate)-2,3-benzodiazepine; HA966 (+)-3-amino-1-hydroxypyrrolit-2-one; 3-HPG: (RS)-3-hydroxyphenylglycine;

IDRA 21: 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide; JST: Joro spider toxin;

LY215490: (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5yl)ethyl]decahydroisoquinoline-3-carboxylic acid; LY262466: DL-2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)-propanoic acid;

LY326325: (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid;

LY354740: (2)-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;

LY367385: (S)-(+)--amino-4-carboxy-2-methylbenzeneacetic acid;

MAP4: (S)-2-amino-2-phosphonobutanoic acid;

MCPG: (+)-alpha-methyl-4-carboxyphenylglycine;

Memantine: 1-amino-3,5-dimethyladamantane;

MPEP: 6-methyl-2- (phenylethynyl)-pyridine;

MPPG: (RS)--Methyl-4-phosphonophenylglycine;

MSOP: (RS)-a-Methylserine-O-phosphate;

MTPG: (RS)--Methyl-4-tetrazolylphenylglycine;

MK-801: (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate; NBQX: 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline; NMDA: N-methyl-D-aspartate;

NPC 12626: 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid; NS-102: 5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime; PCP: phencyclidine;

SYM 2206: (±)-4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine; tADA: trans-azetidine-2,4-dicarboxylic acid; TCP: 1-(2-thienyl)-cyclohexyl piperidine.

YM90K: 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione

Other abbreviations:

PLC (phospholipase C)

PLD (phospholipase D)

cAMP (cyclic aminotrisphosphate)

1: Ca2+ permeability only for AMPA receptors that do not contain R2 2: Ca2+ permeability only for GluR6 containing kainate receptors receptors are undoubtedly the most famous glutamate receptor in the field of learning and memory. The receptor and its associated channel have two properties that render it particularly interesting: firstly, it has a high calcium permeability thus providing access to Ca2+-dependent second messenger cascades relevant to memory formation; secondly, it contains a voltage-gated magnesium block, which requires simultaneous opening of other depolarising conductances to permit activation.166 Accordingly, coincident activity as it is postulated to occur in Hebbian types of synaptic plasticity can be detected by NMDA receptors. In addition, there is a receptor site for the coagonist glycine and various additional modulatory sites. Of potential interest is the modulatory site within the actual ion channel pore, which provides a use-dependent target for drug development with the potential to modify memory formation (see Table 1).

Metabotropic Glu receptors have been identified in the mid-80s. To date, 3 main classes with different molecular and pharmacological properties have been characterised. Links to different second-messenger cascades (see Table 1) provide access to multiple enzymes, immediate early genes and the production of novel proteins, as well as to the modulation of diverse ion channels (reviewed in refs. 7,48,85,177). Depending on the location of these receptors (e.g., pre or postsynaptic, on GABAergic or glutamatergic neurones) both enhancements and reduction of neuronal excitability is possible. As a general rule, group I mGlu receptors tend to promote excitation while group II/III are more prone to reduce it. In addition, the existence of additional, so far unidentified mGlu receptors such PLD coupled or presynaptic group I mGlu receptors has also been suggested.87

In the context of learning and memory, group I mGlu receptors, which couple to phospho-lipase C and hence to intracellular Ca2+ signalling and protein kinase C activation have attracted more interest than group II/III, coupling to adenylate cylclase. Another property of group I mGlu receptors, namely their perisynaptic location,15,1 4 is a further reason for the assumed role in memory formation: similar to NMDA receptors, coincident neuronal excitation and subsequent glutamate 'spillover' may be required to activate these receptors.

One obstacle in pharmacological approaches to study glutamate receptor functions in learning and memory research has been the neurotoxic potency of the vast majority of glutamate receptor agonists and even of some of the antagonists. Therefore, other strategies have focussed on glutamate receptor modulators, and, more recently, on genetically modified animals.

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