4 ± 0.4 pA, n = 3,15; WT 5.2 ± 0.4, n = 3, 15; p = 0.5, t test; Figure 3C). In contrast, the input/output relationship for the eEPSC was significantly different in NARP−/− and wild-type mice (one-way ANOVA, F1,299 = 10.93, p = 0.0011; Figure 3E), and the amplitude of the maximal eEPSC was significantly reduced (NARP−/− 3.35 ± 0.12 pA, n = 3, 24; WT 2.76 ± 0.17, n = 3, 24; p = 0.010, t test; Figure 3F). Thus, the absence of NARP decreased the strength of total excitatory drive onto FS (PV) INs, without affecting the strength of inhibitory output evoked by depolarization of FS (PV) INs. We predicted that the decrease in excitatory drive from pyramidal neurons

to FS (PV) INs in NARP−/− mice would reduce the ability to recruit fast perisomatic inhibition and increase overall cortical excitability. To test this hypothesis, we examined single unit spiking output in the binocular region of Cilengitide price the primary visual cortex of P28 mice in vivo. In NARP−/− mice, visually-evoked activity of neurons in layer II/III (response to 1 Hz reversals of 0.04 cycles/degree;

100% contrast this website gratings; presented at preferred orientation) had a larger average spike rate (median-evoked activity ± SEM [spikes/s]: WT 2.45 ± 0.32, n = 6,16; NARP−/− 4.32 ± 0.34, n = 6, 21; Figure 4D), an earlier time-to-peak (average time-to-peak ± SEM [ms]: WT 132 ± 6, n = 6, 16; NARP−/− 117 ± 7, n = 6, 21; Figure 4E) and a longer duration (average ms ± SEM: WT 76 ± 5, n = 6,16; NARP−/− 101 ± 6, n = 6, 21; Figure 4F) than wild-types. To ask if enhancing inhibitory output could reverse this cortical hyperexcitability, we administered diazepam, a positive allosteric modulator of ligand-bound GABAA receptors (Sieghart, 1995). In both WT and NARP−/− mice, acute diazepam (15 mg/kg, intraperitoneally [i.p.]) significantly reduced the average spike rate (evoked: WT + DZ 1.16 ± 0.13, n = 6, 25; NARP/ + DZ 2.98 ± 0.40, n = 6, 17; Figure 4D), the time-to-peak (WT

+ DZ 153 ± 4, n = 6, 25; NARP/ + DZ, 139 ± 4, n = 6, 17; Figure 4E), and the response duration of visually-evoked activity (WT + DZ 54 ± 3, n = 6,25; NARP/ + DZ 78 ± 5, n = 6,17; Figure 4F). In all cases, we observed parallel changes in spontaneous and evoked neuronal firing rates, resulting in no net change in signal-to-noise until ratio (evoked activity/[evoked activity + spontaneous activity] average ± SEM: WT 0.74 ± 0.03, n = 6, 16; NARP−/− 0.75 ± 0.03, n = 6, 21; WT + DZ 0.74 ± 0.03, n = 6, 25; NARP−/− + DZ 0.80 ± 0.03, n = 6, 17; Kruskal-Wallis test, H(3) = 2.201, p = 0.532). Similar enhancement of visually-evoked and spontaneous activity was observed in neurons from layer IV of NARP−/− mice (Figure S2), indicating widespread hyperexcitability in the primary visual cortex of NARP−/− mice. We used visually evoked potentials (VEPs) to ask if the absence of NARP, and the resulting increase in cortical excitability, impacted visual acuity or visual cortical plasticity.