Glycine-induced long-term potentiation is associated with structural and functional modifications of a-amino-3-hydroxyl-5- methyl-4-isoxazolepropionic acid receptors (hippocampusyplasticityycalpainyglutamateyspectrin)

Global long-term potentiation (LTP) was induced in organotypic hippocampal slice cultures by a brief application of 10 mM glycine. Glycine-induced LTP was occluded by previous theta burst stimulation-induced poten- tiation, indicating that both phenomena share similar cellular processes. Glycine-induced LTP was associated with increased ( 3 H)a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) binding in membrane fractions as well as increased amount of a selective spectrin breakdown product generated by calpain-mediated spectrin proteolysis. Antibodies against the C-terminal (C-Ab) and N-terminal (N-Ab) domains of GluR1 subunits were used to evaluate structural changes in AMPA receptor properties resulting from glycine-induced LTP. No quantitative or qualitative changes were observed in Western blots from membrane fractions prepared from gly- cine-treated slices with C-Ab. In contrast, Western blots stained with N-Ab revealed the formation of a 98-kDa species of GluR1 subunits as well as an increased amount of immu- noreactivity after glycine-induced LTP. The amount of spec- trin breakdown product was positively correlated with the amount of the 98-kDa species of GluR1 after glycine treat- ment. Functional modifications of AMPA receptors were evaluated by determining changes in the effect of pressure- applied AMPA on synaptic responses before and after glycine- induced LTP. Glycine treatment produced a significant in- crease in AMPA receptor function after potentiation that correlated with the degree of potentiation. The results indicate that LTP induction produces calpain activation, truncation of the C-Ab domain of GluR1 subunits of AMPA receptors, and increased AMPA receptor function. They also suggest that insertion of new receptors takes place after LTP induction. Long-term potentiation (LTP) is an attractive candidate for a cellular mechanism of learning and memory as it exhibits many features expected for such a mechanism. It is induced by patterns of stimulation similar to those found in animals exploring novel environments; it is very long lasting (weeks in chronic preparations), and its pharmacology matches that of learning and memory (1, 2). It is generally agreed that LTP induction requires N-methyl-D-aspartate (NMDA) receptor activation, resulting in increase in postsynaptic calcium con- centration and in the activation of several biochemical cas- cades leading to increased synaptic efficacy (3, 4). Possible mechanisms for LTP expression, in particular whether LTP is expressed as an increase in neurotransmitter release or by modifications of postsynaptic elements, are still a matter of debate (5-7). Over the last 10-15 years, a large body of