N-methyl-D-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABA(A) receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.

UBE3A encodes the ubiquitin ligase E6-AP and the point mutation of this gene causes severe neurological disorder called Angelman Syndrome (AS) in a young child. To elucidate the molecular basis of AS pathogenesis and promote the design of rational therapies for AS patient, an Ube3a null mutation mouse, which recapitulated the development and behavioural defects of human patients, was generated. The mice with maternal deficiency (m-/p+) for Ube3a display several features of AS, including microcephaly, motor dysfunction, inducible seizures, abnormal hippocampal EEG and deficits in context-dependent learning. Based on the knowledge of altered UBE3A expression profile and uncoordinated movement observed in AS patients, I hypothesized that the normal function and electrophysiological properties of Purkinje neurons (PNs), which provide the sole output of cerebellar cortex might be affected by the deletion of E6-AP. The electrophysiological studies on PNs of AS mouse would be able to provide meaningful information on deciphering the molecular basis for the learning and memory deficit in AS and be helpful for developing effective drugs. Thus, in the first part of this thesis, the physiological properties of cerebellar cortex in Ube3a null mutation mice were thoroughly examined. The data collected from acute cerebellar slices showed that the intrinsic excitability, the inhibitory synaptic transmission and basal excitatory synaptic transmission were normal in the mutant mice. There was also no alteration in a type of long-term potentiation (LTP) that is presynaptically expressed at PF (parallel fiber)-PN synapses. In contrast, another type of LTP, which expressed postsynaptically at the same PF-PN synapses, was impaired, and another type of synaptic plasticity, long-term depression (LTD), III