Plasticity of rat central inhibitory synapses through GABA metabolism

1. The production of the central inhibitory transmitter GABA (gamma -aminob utyric acid) varies in response to different patterns of activity. It there fore seems possible that GABA metabolism can determine inhibitory synaptic strength and that presynaptic GABA content is a regulated parameter for syn aptic plasticity. 2. We altered presynaptic GABA metabolism in cultured rat hippocampal slice s using pharmacological tools. Degradation of GABA by GABA-transaminase (GA BA-T) was blocked by gamma -vinyl-GABA (GVG) and synthesis of GABA through glutamate decarboxylase (GAD) was suppressed with 3-mercaptopropionic acid (NIPA). We measured miniature GABAergic postsynaptic currents (mIPSCs) in C A3 pyramidal cells using the whole-cell patch clamp technique. 3. Elevated intra-synaptic GABA levels after block of GABA-T resulted in in creased mIPSC amplitude and frequency. In addition, tonic GABAergic backgro und noise was enhanced by GVG. Electron micrographs from inhibitory synapse s identified by immunogold staining for GABA confirmed the enhanced GABA co ntent but revealed no further morphological alterations. 4. The suppression of GABA synthesis by HPA had opposite functional consequ ences: mIPSC amplitude and frequency decreased and current noise was reduce d compared with control. However, we were unable to demonstrate the decreas ed GABA content in biochemical analyses of whole slices or in electron micr ographs. 5. We conclude that the transmitter content of GABAergic vesicles is variab le and that postsynaptic receptors are usually not saturated, leaving room for up-regulation of inhibitory synaptic strength. Our data reveal a new me chanism of plasticity at central inhibitory synapses and provide a rational e for the activity-dependent regulation of GABA synthesis in mammals.