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The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of <jats:italic>Atrx<\/jats:italic> loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of <jats:italic>Atrx<\/jats:italic> in postnatal forebrain excitatory neurons (ATRX\u2010cKO) causes deficits in long\u2010term hippocampus\u2010dependent spatial memory. Thus, we hypothesized that ATRX\u2010cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane\u2010anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired\u2010pulse facilitation (PPF) at 50\u2010ms interpulse interval, and by their long\u2010term potentiation (LTP) induced by theta\u2010frequency burst stimulation. Baseline single\u2010pulse excitatory response at each synapse did not differ between ATRX\u2010cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX\u2010cKO mice. While basal dendritic LTP of the first\u2010pulse excitatory response was not affected in ATRX\u2010cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long\u2010term spatial memory deficits in ATRX\u2010cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR\u2010X syndrome patients.<\/jats:p>","DOI":"10.1002\/hipo.23174","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T13:26:39Z","timestamp":1573565199000},"page":"565-581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity"],"prefix":"10.1002","volume":"30","author":[{"given":"Radu","family":"Gugustea","sequence":"first","affiliation":[{"name":"Graduate Program in Neuroscience Western University  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee J.","family":"Tamming","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Western University  London Ontario Canada"},{"name":"Department of Paediatrics Western University  London Ontario Canada"},{"name":"Division of Genetics and Development Children's Health Research Institute  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Martin\u2010Kenny","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Western University  London Ontario Canada"},{"name":"Division of Genetics and Development Children's Health Research Institute  London Ontario Canada"},{"name":"Department of Anatomy and Cell Biology Western University  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie G.","family":"B\u00e9rub\u00e9","sequence":"additional","affiliation":[{"name":"Graduate Program in Neuroscience Western University  London Ontario Canada"},{"name":"Department of Paediatrics Western University  London Ontario Canada"},{"name":"Division of Genetics and Development Children's Health Research Institute  London Ontario Canada"},{"name":"Department of Anatomy and Cell Biology Western University  London Ontario Canada"},{"name":"Department of Oncology, Schulich School of Medicine and Dentistry Western University  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8887-4869","authenticated-orcid":false,"given":"L. 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