Cognitive impairment occurs and is more prevalent during primary progressive MS[1]. While MS clinical presentation is protean, epidemiological studies have revealed that MS patients are three to six times more likely to develop epileptic seizures than the population at large. Excitotoxic neuronal damage in the hippocampus (and other regions) is thought to be one of the causes for cognitive deficits in nearly 50% of multiple sclerosis (MS) patients and could be due glutamate dyshomeostasis. Glutamate is a major excitatory neurotransmitter in the mammalian CNS. Our recent published results have shown i) a decrease in inhibitory parvalbumin neurons of chronic cuprizone-diet fed demyelinating mice (Lapato et al., 2016) and in the hippocampus of MS patients with seizures (Lapato et al., 2020); ii) astrocyte glutamate uptake and water homeostasis are dysregulated in the hippocampus of MS patients with seizures (Lapato et al., 2020)[4]. The objective of this application is to understand how demyelination-induced loss of inhibitory neurons impacts hippocampal changes that lead to learning and memory deficits. We hypothesize that chronic demyelination induces decrease in hippocampus PV neurons and indices substantial changes in synaptic transmission involved in learning and memory. In aim 1: we will determine chronic cuprizone diet-demyelination induced changes in long term potentiation by electrophysiology in brain slices. In aim 2, we will examine synaptic changes during chronic demyelination in the CA1 and striatum radiatum regions of the hippocampus. In aim 3, we will assess chronic demyelination induced changes in learning and memory. We anticipate that this research will be transformative, as we will introduce to the research community a functional and molecular mechanism for memory disorder due to demyelination.