Autistic spectrum disorder (ASD) has been associated with genetic alterations of synaptic proteins such as the point mutation R451C in neuroligin 3 (NLGN3), a postsynaptic adhesion molecule located at both excitatory and inhibitory synapses. By exploiting the transgenic NLGN3-R451C knock-in (KI) mice, an animal model of ASD, we investigated this mutation in the coordination of excitatory and inhibitory synaptic plasticity. In hippocampal primary cultures, while the NLGN3-R451C protein was less expressed in KI mice with respect to WT, the molecular and functional properties of basal excitatory and inhibitory synaptic transmission were comparable in both genotypes. In contrast, a chemical protocol consisting in the application of NMDA depressed excitatory glutamatergic synapses (LTD) and potentiated inhibitory GABAergic synapses (iLTP) in WT mice. These effects were paralleled by changes in synaptic receptors and scaffold proteins at both excitatory and inhibitory synapses. Interestingly, both the NMDA-induced LTD and iLTP along with the modifications in synaptic receptor and scaffold protein content were absent in KI mice. Moreover, in hippocampal slices, inhibitory postsynaptic currents induced by the optogenetic activation of PV+ interneurons were potentiated in WT mice by the plasticity-inducing protocol consisting of the 10-second depolarization of the postsynaptic neuron, while in KI mice the same protocol failed to induce a significant increase of synaptic current amplitude. Collectively, our results reveal that the perturbed synaptic molecular composition of both glutamatergic and GABAergic synapses induced by the NLGN3-R451C mutation disrupts the coordination of excitatory and inhibitory synaptic plasticity thus potentially contributing to the pathophysiology of ASD.