biostudies-literatureScala FNational Center for Advancing Translational SciencesNCATS NIH HHSNational Institutes of Health (NIH NIMH R01 MH095995 to Fernanda Laezza)NIMH NIH HHSTranslational Sciences at the University of Texas Medical BranchAlzheimer's AssociationUniversità Cattolica886-900https://www.ebi.ac.uk/biostudies/studies/S-EPMC4801354biostudies-literatureUnknown36(2)Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K(+) currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K(+) currents, at Ser-Neurobiology of agingIntraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3.PMC4801354R01 MH095995UL1TR000071UL1 TR000071NIRG-14-321307Scala FSpinelli MLaezza FD'Ascenzo MRipoli CPiacentini RGrassi CFusco SLi Puma DDfalseIntraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3.Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K(+) currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K(+) currents, at Ser-2015-01-01T00:00:00Z2015 Feb2025-04-26T01:55:45.128Z2019-03-27T03:09:57ZS-EPMC48013542554142210.1016/j.neurobiolaging.2014.10.034