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Valproic acid (<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>) attenuates senile plaques and neuronal loss. Here, we confirmed that <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> treatment improved spatial memory in amyloid precursor protein (<jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content>)\/presenilin 1 (PS 1) double\u2010transgenic mice and investigated the effect of <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> on synaptic structure and neurite outgrowth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used ultrastructural analysis, immunocytochemistry, immunofluorescence staining, and Western blot analysis to assess the effect of <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> treatment in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> treatment thickened the postsynaptic density, increased the number of presynaptic vesicles, and upregulated the expression of synaptic markers <jats:styled-content style=\"fixed-case\">PSD<\/jats:styled-content>\u201095 and <jats:styled-content style=\"fixed-case\">GAP<\/jats:styled-content>43. <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> increased neurite length of hippocampal neurons <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. In <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>\u2010treated <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> mouse brain, inactivated <jats:styled-content style=\"fixed-case\">GSK<\/jats:styled-content>\u20103\u03b2 (<jats:styled-content style=\"fixed-case\">pS<\/jats:styled-content>er9\u2010<jats:styled-content style=\"fixed-case\">GSK<\/jats:styled-content>\u20103\u03b2) was markedly increased, while hyperphosphorylation of tau at Ser396 and Ser262 was decreased; total tau levels remained similar. <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> treatment notably improved <jats:styled-content style=\"fixed-case\">pS<\/jats:styled-content>er133\u2010<jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> response element\u2010binding protein (<jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content>) and brain\u2010derived neurotrophic factor (<jats:styled-content style=\"fixed-case\">BDNF<\/jats:styled-content>) levels, which are associated with synaptic function and neurite outgrowth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> improves behavioral deficits in <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>, modifies synaptic structure, and accelerates neurite outgrowth, by inhibiting the activity of <jats:styled-content style=\"fixed-case\">GSK<\/jats:styled-content>\u20103\u03b2, decreasing hyperphosphorylated tau, enhancing <jats:styled-content style=\"fixed-case\">CREB<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">BDNF<\/jats:styled-content> expression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12445","type":"journal-article","created":{"date-parts":[[2015,9,19]],"date-time":"2015-09-19T07:09:32Z","timestamp":1442646572000},"page":"887-897","source":"Crossref","is-referenced-by-count":60,"title":["Valproic Acid Modifies Synaptic Structure and Accelerates Neurite Outgrowth Via the Glycogen Synthase Kinase\u20103\u03b2 Signaling Pathway in an Alzheimer's Disease Model"],"prefix":"10.1111","volume":"21","author":[{"given":"Zhi\u2010Min","family":"Long","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Neurobiology Chongqing Medical University Chongqing China"},{"name":"Department of Anatomy Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Neurobiology Chongqing Medical University Chongqing 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