By exclusion, our data suggest a reduction in the total number of functional inhibitory synapses. Our previous observations of reduced inhibition were made in Ube3am−/p+ mice on the 129Sv/Ev strain, which are susceptible to spontaneous seizures ( Jiang et al., 1998), making it difficult to determine whether

the synaptic abnormalities were a cause or result of seizures ( Sloviter, 1987). To address this concern, we tested for possible synaptic deficits in Ube3am−/p+ mice maintained on the C57BL/6J strain, which have a low incidence of evoked seizures and INCB024360 mw no reported spontaneous seizures ( Jiang et al., 1998). We performed mIPSC recordings at P80 in WT and Ube3am−/p+ C57BL/6J mice to test if synaptic defects arose in the absence of spontaneous seizures. As before, we observed no genotypic differences in the amplitude of mIPSCs, but a large decrease in mIPSC frequency in Ube3am−/p+ mice ( Figure 2A). We also performed mEPSC recordings in L2/3 pyramidal neurons in mice on the C57BL/6J

strain to confirm previous results from the 129Sv/Ev strain ( Yashiro et al., 2009). Consistent with previous results, there was a significant decrease in mEPSC frequency, but not amplitude, between Ube3am−/p+ and WT mice ( Figure 2B). These observations reveal that Ube3am−/p+ L2/3 pyramidal neurons have a 50% reduction in spontaneous inhibitory synaptic Akt inhibitor activity, medroxyprogesterone but only a 28% decrease in excitatory synaptic activity. Additionally, intrinsic excitability of L2/3 pyramidal neurons was increased in Ube3am−/p+ mice compared to

WT ( Figure S1C). Together these data suggest that a disproportionate loss of inhibition may lead to an excitatory/inhibitory imbalance in Ube3am−/p+ L2/3 pyramidal neurons. Ube3a is expressed by both excitatory and inhibitory interneurons in the cerebral cortex (Sato and Stryker, 2010). Therefore, Ube3a loss might be expected to affect both neuron classes. To assess this possibility, we recorded spontaneous synaptic activity in fast-spiking (FS) inhibitory interneurons, which we identified by membrane properties, aspinous dendrites, and characteristic high firing rates (Okaty et al., 2009). FS inhibitory interneurons in L2/3 were targeted for whole-cell recording at P80, an age at which excitatory and inhibitory neurotransmission onto L2/3 pyramidal neurons is altered. In contrast to L2/3 pyramidal neurons, the loss of Ube3a did not affect either the amplitude or the frequency of mIPSCs onto FS inhibitory interneurons (Figure 2C). Moreover, excitatory connections onto FS inhibitory interneurons appeared normal, as Ube3a loss did not alter mEPSC amplitude or frequency (Figure 2D).