Hippocampal Interneurons are heavily myelinated but show differences in composition/distribution and myelin function. Contactin-2 (CNTN2 or TAG-1), an adhesion molecule of the immunoglobulin superfamily, expressed in glia and axons, organizes the juxtaparanodal region of myelinated fibers and clusters voltage-gated potassium channels under the myelin sheath. CNTN2 has a dynamic spatial and temporal expression and is implicated in migration during development as well as in neuropathology (multiple sclerosis, AD). We have shown that a significant population of hippocampal GABAergic interneurons (parvalbumin (PV+) and somatostatin (SST+)) expresses CNTN2 and recently published that Cntn2-deficient interneuron populations in vivo exhibit decreased Kv1.2 channel clustering at the nodes of Ranvier. Here we report that SST+ interneurons are hypomyelinated in Cntn2-deficient mice by IMARIS software analysis. Furthermore, patch-clamp recordings show that SST+ interneuron excitability decreases in Cntn2-deficient mice while spontaneous inhibitory postsynaptic currents on pyramidal neurons increase. These functional impairments can be attributed to myelin deficits or to alterations in hippocampal synaptic regulation or both. We also show that CNTN2 is present in synaptoneurosomes and synaptic compartments by biochemical and advanced imaging assays. Furthermore, we show that Cntn2-deficient mice are significantly impaired in their long-term potentiation (LTP) profile, indicating the significance of CNTN2 in plasticity. Proteomic analysis (mass spectrometry, single-cell analysis) is in progress to provide mechanistic insights on the novel role of CNTN2 in synaptic plasticity using our conditional Cntn2-deficient mice which will further be employed in behavioral assessment. We highlight the role of CNTN2 and its implication in hippocampal interneuron physiology and myelination.