Neuronal activity can modify the efficacy of synaptic transmission. This use-dependent change in synaptic strength may alter information processing in neuronal circuitry and information storage in the brain, and is believed to underlie learning and memory. Much of the effort in this field focuses on the longer-term potentiation and depression at excitatory glutamatergic synapses. However little is known about how inhibitory synaptic transmission is regulated. Inhibitory synapses control the timing and firing patterns of the postsynaptic neuron. Thus a lasting alteration in the strength of inhibitory synaptic transmission can alter the excitability of the postsynaptic neuron changing information processing within a neuronal circuit. Such changes are essential for both the physiological functioning of the brain and for the alterations in neuronal excitability that occur under pathological conditions such as epilepsy. For example enhancing GABA transmission can control epilepsy in many patients, while blocking GABAergic neurotransmission generates seizures. Our recent work shows that repetitive activation of excitatory synaptic inputs in the cerebellum results in a long-lasting increase in the secretion of an inhibitory transmitter, GABA, from a cerebellar interneuron, the stellate cell. This change requires activation of NMDA-type glutamate receptors in stellate cells and enhances the inhibitory synaptic response to GABA in the postsynaptic cell. We propose to study the mechanisms underlying the activity-dependent change in GABA release. In this study, we plan to address the following questions. First, can this form of plasticity also be induced at the stellate/basket cell to Purkinje cell synapse and at the synapse between stellate cells? Second, which subtypes of NMDA receptors are involved in the induction of the lasting increase in GABA release from cerebellar stellate cells? Third, what are the molecular events that are responsible for NMDA receptor-induced enhancement of GABA release? Our investigation of cellular and molecular mechanisms underlying activity-dependent change in inhibitory transmission could contribute to our understanding of cellular mechanisms underlying motor learning and the neurological disorders that is associated with changes in GABAergic transmission. ? ?
