We next wondered whether the increased activity observed in

We next wondered whether the increased activity observed in

pyramidal cells of Erbb4 mutants could also enhance their excitatory drive onto fast-spiking interneurons. To this end, we recorded sEPSCs from PV+ fast-spiking interneurons ( Figure 4D) and observed a significant increase in sEPSC frequencies in Erbb4 mutant interneurons compared to control AZD2014 in vitro cells, with no changes in their amplitude ( Figures 4E and 4F). Interestingly, we found a significant increase in the NMDA/AMPA ratio of these currents (control: 0.26 ± 0.05; Erbb4 mutant: 0.66 ± 0.14; n = 8 neurons per genotype from three mice in each case; p < 0.05, t test), which was caused by a significant reduction in the amplitude of AMPA selleck screening library currents in Erbb4 mutant interneurons (control: 257 ± 87 pA; Erbb4 mutant: 69 ± 12 pA; p < 0.05, t test). Because we did not observe any difference in the amplitude of mEPSCs recorded from fast-spiking interneurons ( Figure 1Q), these results suggested that the excitatory synapses that are lost from PV+ interneurons in Erbb4 mutants are preferentially enriched in AMPA receptors. To examine the activity of PV+ fast-spiking interneurons, we performed current-clamp recordings and found no significant alterations in the basic membrane properties of the PV+ fast-spiking interneurons in Erbb4 mutants compared to control

mice in response to 500 ms depolarizing steps ( Table S1). However, we observed that most PV+ interneurons displayed a delay to the first spike at threshold potential for spikes in Erbb4 mutants (n = 9/10 cells) compared to controls (n = 5/11 cells). Most PV+ interneurons also spontaneously fired at resting membrane potential in both controls (n = 7/11 cells) and Erbb4 mutants (n = 9/10 cells). However, we found that the 17-DMAG (Alvespimycin) HCl mean spontaneous firing frequency of PV+ fast-spiking interneurons is largely increased

in the absence of ErbB4 ( Figures 4G and 4H). Moreover, application of 5 s depolarizing ramps revealed a lower rheobase in the Erbb4 mutant PV+ interneurons than controls ( Figures 4I and 4J) without changes in the threshold potential for spikes (Lhx6-Cre;Erbb4+/+;RCE controls, −42.9 ± 3.6 mV; Lhx6-Cre;Erbb4F/F;RCE mutants, −48.1 ± 3.0 mV; p = 0.3, t test). This enhanced excitability leads to a significant increase in the number of action potentials elicited during the ramp by the PV+ fast-spiking interneurons (Lhx6-Cre;Erbb4+/+;RCE controls, 23 ± 8; Lhx6-Cre;Erbb4F/F;RCE mutants, 102 ± 26; p < 0.05, t test). Altogether, these results suggested that the loss of specific synapses in Erbb4 mutants leads to a concomitant enhancement in the activity of both pyramidal cells and fast-spiking interneurons. To identify the potential consequences of these network alterations in vivo, we carried out local field potential (LFP) recordings in the hippocampus of urethane-anesthetized control and conditional Erbb4 mutant mice.

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