title: Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.
abstract: Using a genetic mouse model that faithfully recapitulates aDISC1genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit Kv1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of Kv1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.SIGNIFICANCE STATEMENTSchizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes,DISC1, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, and.
authors.forename: Gregg W
authors.initials: GW
authors.lastname: Crabtree
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, and.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, and.
authors.forename: Mirna
authors.initials: M
authors.lastname: Kvajo
authors.affiliation: Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, United Kingdom.
authors.forename: Jantine A C
authors.initials: JA
authors.lastname: Broek
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, and.
authors.forename: Karine
authors.initials: K
authors.lastname: Fénelon
authors.affiliation: Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, New York, New York 10032.
authors.forename: Heather
authors.initials: H
authors.lastname: McKellar
authors.affiliation: Florida State University School of Medicine, Tallahassee, Florida 32304.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Departments of Psychiatry and.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 1QT, United Kingdom.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214.
authors.forename: James M
authors.identifier: 0000-0002-8994-7588
authors.initials: JM
authors.lastname: O'Donnell
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, and jag90@cumc.columbia.edu.|Neuroscience, Columbia University Medical Center, New York, New York 10032, and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins
keywords: Disc1 mouse model; Kv channels; excitability; prefrontal cortex; schizophrenia; synaptic plasticity