00 ± 0.11, n = 5). Increasing inhibitory output with diazepam for the last 5 days of chronic monocular deprivation enabled an ocular dominance shift in adult NARP−/− mice (15 mg/kg, i.p.; cMD + DZ 1.17 ± 0.10, n = 6; Figure 7). As expected, adult wild-type mice expressed a significant shift in contralateral bias MK-8776 datasheet in response to prolonged (7 days) and chronic (80 days) monocular deprivation (VEP amplitude contralateral eye/ipsilateral eye average ± SEM: adult WT no MD 2.04 ± 0.20,

n = 5; 7 days MD 1.14 ± 0.13, n = 5; cMD 0.99 ± 0.17, n = 3), which was unaffected by diazepam in adulthood (cMD + DZ 0.98 ± 0.09, n = 4). Thus, in the absence of NARP, the visual system is unable to respond to monocular deprivation, despite functional inhibitory output. Although NARP−/− mice do not express ocular dominance plasticity, other forms of experience-dependent synaptic plasticity, such as the plasticity of the VEP contralateral bias, remain intact

(Figure 5). To further explore the range of deficits in synaptic plasticity in NARP−/− mice, we examined the response to repetitive visual stimulation, previously shown to induce robust changes in VEP amplitudes in vivo (Sawtell et al., 2003, Frenkel et al., 2006, Ross et al., 2008, Cooke and Bear, 2010 and Beste et al., 2011). High-frequency visual stimulation (10 Hz reversals of 0.04 cycles/degree, 100% contrast, vertical gratings) induced a rapid enhancement of the VEP amplitude in P30 NARP−/− and wild-type mice (VEP amplitude 60 min poststimulation normalized to prestimulation: WT 1.48 ± 0.12, n = 5; NARP−/− 1.41 ± 0.06, n = 5; two-way ANOVA, selleck compound F1,1 = 0.316, p = 0.584; Figure 8A). The enhancement in VEP amplitude was dependent on the temporal frequency of the visual stimulation, as visual stimulation at an intermediate temporal frequency (5 Hz) did not affect VEP amplitudes in either genotype (VEP amplitude 60 min poststimulation normalized to prestimulation: WT 1.00 ± 0.03, n = 3; NARP−/− 0.97 ± 0.10, n = 3). The increase in VEP amplitude induced Urease by 10 Hz visual stimulation was specific for the orientation of the visual stimulus, as no VEP

enhancement was observed in response to a rotated grating (10 Hz: WT 0.96 ± 0.05, n = 5; NARP−/− 0.94 ± 0.06, n = 5; 5 Hz: WT 0.94 ± 0.03, n = 3; NARP−/− 0.97 ± 0.08, n = 3; two-way ANOVA, F1,1 = 0.002, p = 0.968; Figure 8B). In contrast, low-frequency visual stimulation (1 Hz reversals of 0.04 cycles/degree, 100% contrast vertical gratings) induced a slowly emerging increase in VEP amplitude in wild-type mice (VEP amplitude post-/prestimulation: 12 hr 0.98 ± 0.14; 15 hr 1.32 ± 0.12; 18 hr 1.45 ± 0.08; n = 5), that was inhibited by diazepam (12 hr 0.91 ± 0.01; 15 hr 0.91 ± 0.04; 18 hr 1.13 ± 0.01; n = 5, two-way ANOVA with repeated-measures, F1,8 = 18.288, p = 0.003; ∗p < 0.01 versus wild-type control; Figure 8C).