Mental retardation (MR) is a common disorder affecting 2-3% of the general population; a leading cause of moderate to severe MR is mutations of genes located on the X-chromosome. One gene implicated in X-linked mental retardation (XLMR) is the OPHN1 (Ophn-1 in mice) gene which encodes oligophrenin-1, a RhoGAP protein. Loss of function mutations upregulate Rho GTPase-dependent signalling pathways leading to altered actin cytoskeleton dynamics which are important in vesicle dynamics and dendritic spine structure. In addition to its function in regulating actin dynamics, oligophrenin-1 regulates the kinetic efficiency of clathrin-mediated endocytosis of synaptic vesicles leading to reduced repetitive activation in inhibitory synapses. As neuronal synchrony in the hippocampus plays a role in encoding and retrieving episodic memory and attention, we hypothesised that alterations in synaptic vesicle availability will alter neuronal synchronisation and could underlie the reduced cognitive performance of Ophn-1 null mice. Ophn-1 mice (male 15-30g, 3-10 weeks old) were anaesthetised by I.P. injection of medetomidine (1mg/kg) and ketamine (76mg/kg). Values are expressed as mean±S.E.M, compared by ANOVA or Student’s t-test. Initial experiments tested if oligophrenin-1 functioned as a regulator of vesicle availability in hippocampal CA3 synapses. Whole cell patch-clamp recordings from CA3c pyramidal neurons revealed that the frequency of spontaneous EPSCs and IPSCs (excitatory postsynaptic currents and inhibitory postsynaptic currents) was lower in Ophn-1-/y than Ophn-1+/y neurons (sEPSCs: 1.67±0.37 Hz, n=9; 6.91±1.50 Hz n=8, p=0.003; sIPSCs: 8.78±0.81 Hz, n=7; 12.63±0.76 n=7, p=0.009, respectively). Consistent with reduced spontaneous transmission, evoked IPSCs were significantly smaller in Ophn-1-/y neurons than Ophn-1+/y neurons (1573.3±172.5 pA, n=15 and 2316.9±278.6 pA, n=13, respectively; p=0.02). As neuronal synchrony is dependent on the ability of inhibitory synapses to follow repetitive activation, we examined whether secretory vesicle availability was altered in Ophn-1 null slices at frequencies relevant to cognition. Inhibitory synapses were stimulated at 33 Hz; IPSCs built up with successive stimuli, reaching a steady level within 10 stimuli in Ophn-1+/y neurons; IPSC facilitation was much weaker in Ophn-1-/y neurons (p=0.001). We tested whether this inability to follow repetitive stimulation was a result of a reduced readily releasable pool (RRP) of synaptic vesicles. The RRP was smaller in Ophn-1-/y than Ophn-1+/y synapses (513.8±100.9 pA, n=7 and 1466.2±307.7 pA, n=5, respectively, p=0.005), corresponding to a smaller number of vesicles in the RRP (12±2 and 35±7, respectively). Gamma oscillations can be generated in vitro in the CA3 region of the hippocampus by tonic activation of kainate receptor or can occur spontaneously. Spontaneous gamma activity was smaller in Ophn-1-/y slices than in Ophn-1+/y slices (27.5±7.6 μV2, n=8 and 66.0±13.7 μV2, n=10, respectively, p=0.03). Superfusion of KA (50 nM) increased CA3 network activity throughout its application in both Ophn-1+/y and Ophn-1-/y slices. KA-induced gamma oscillations were significantly smaller in Ophn-1-/y slices than in Ophn-1+/y slices (2910.1±521.3 μV2, n=21 and 5906.2±936.9 μV2, n=30, respectively, p=0.02). We have previously shown that the synaptic deficits in Ophn-1-/y neurons are reversed by acute inhibition of Rho-kinase (ROCK) activity. Application of the ROCK inhibitor, Y-27632 (10 μM, for 20 minutes) significantly increased spontaneous oscillations in Ophn-1-/y slices (vehicle 71.5±19.2 μV2, Y-27632 215.8±51.8 μV2, p=0.005). In Ophn-1+/y slices, Y-27632 did not affect spontaneous oscillations (vehicle 137.5±20.9 μV2, Y-27632 180.8±40.9 μV2, p=0.32). In the present study, we investigate the role of oligophrenin-1 in neuronal network activity; particularly spontaneous- and kainate-induced gamma oscillations using the Ophn-1 mouse model of intellectual disability. We demonstrate that hippocampal inhibitory synapses are unable to function at frequencies necessary for higher cognitive function, due to a substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. We propose that these synaptic changes underlie the deficits in gamma oscillations. The rescue of the emergent neuronal network activity by small molecule pharmacological inhibition of the downstream signalling pathway of oligophrenin-1, raises the possibility of a pharmacotherapy to treat affected individuals.