The ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is widely expressed in the nervous system and is involved in the formation, function, and plasticity of synapses. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allows the formation of trans-synaptic bridges, and triggers transmembrane signaling. We recently reported a homozygous missense variants of GRID1, p.Arg161His, associated with combined intellectual disability, spastic paraplegia and glaucoma. In vitro studies revealed that this mutation hampers metabotropic glutamate receptor mGlu1/5 signaling through Ca2+ and ERK pathways, and impairs dendrite morphology and excitatory synapse density. To evaluate the impact of the mutation in a more integrated landscape, we generated a CRISPR/Cas9 edited mouse line harboring the Arg161His mutation at the GRID1 locus. We performed electrophysiological characterization of synaptic transmission in the CA1 pyramidal cells of the hippocampus using whole cell and field recordings. We observed that miniature excitatory postsynaptic currents where affected in homozygous mice compared to wilt-type animals (WT). Miniature inhibitory synaptic currents remained unchanged. The ratio of AMPA current to NMDA current and the rectification of the I-V relation of AMPA currents were increased in homozygous mice. No change was observed in heterozygous mice. Interestingly, homozygous mice exhibited increased amplitude of NMDA-dependent long term potentiation and group I mGlu-dependent long term depression. These results provide a starting point for the understanding of the pathophysiology of intellectual disability associated with GRID1 variants.