COMPLEX ROLES OF GLUTAMATE IN THE GIBBS-NG MODEL OF ONE-TRIAL AVERSIVE LEARNING IN THE NEWBORN CHICK

Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LTP, a neural phenomenon which may be associa ted with learning and memory formation. Intracerebral injection of lar ge amounts of glutamate between 5 min before and 2.5 min after passive avoidance learning in young chicks inhibits short term memory, which occurs between 0 and 10 min post-learning in a three-stage model of me mory formation first established by Gibbs and Ng (25) [Physiol. Behav. 23:369-375; 1979]. This effect may be attributed to non-specific exci tation. Blockade of glutamate uptake by L-aspartic acid beta-hydroxama te also abolishes this stage of memory, provided the drug is administe red within 2.5 min of learning. Interference with either the productio n of precursors for transmitter glutamate in astrocytes or with glutam ate receptors is also detrimental to memory formation, but the effects appear much later. After its release from glutamatergic neurons, glut amate is, to a large extent, accumulated into astrocytes where it is c onverted to glutamine, which can be returned to glutamatergic neurons and reutilized for synthesis of transmitter glutamate, and partly oxid ized as a metabolic substrate. The latter process leads to a net loss of transmitter glutamate which can be compensated for by de novo synth esis of a glutamate precursor alpha-ketoglutarate (alpha KG) in astroc ytes, a process which is inhibited by the astrocyte-specific toxin flu oroacetate (R. A. Swanson, personal communication). Intracerebral inje ction of this toxin abolishes memory during an intermediate stage of m emory processing occurring between 20 and 30 min post-training (50) [C og. Brain Res. 2:93-102; 1994]. Injection of methionine sulfoximine (M SG), a specific inhibitor of glutamine synthetase, which interferes wi th the re-supply of transmitter glutamate to neurons by inhibition of glutamine synthesis in astrocytes, has a similar effect. This effect o f MSO is prevented by intracerebral injection of glutamate, glutamine, or a combination and alpha KG and alanine. MSO must be administered b efore learning, but does not interfere with acquisition since short-te rm memory remains intact. Administration of either the NMDA antagonist AP5, the AMPA antagonist DNQX, or the metabotropic receptor antagonis t MCPF, also induces amnesia. Memory loss in each case does not occur until after 70 min post-training, during a protein synthesis-dependent long-term memory stage which begins at 60 min following learning. How ever, to be effective, AP5 must be administered within 60 s following learning, MCPG before 15 min post-learning, and DNQX between 15 and 25 min after learning. Together, these findings suggest that learning re sults in an immediate release of glutamate, followed by a secondary re lease of this transmitter at later stages of processing of the memory trace, and that one or both of these increases in extracellular glutam ate concentration are essential for the consolidation of long-term mem ory. Since both fluoroacetate and MSO act exclusively on glial cells, the findings also show that neuronal-glial interactions are necessary during the establishment of memory. Copyright (C) 1996 Elsevier Scienc e Ltd.