title: SK3 Channel Overexpression in Mice Causes Hippocampal Shrinkage Associated with Cognitive Impairments.
abstract: The dysfunction of the small-conductance calcium-activated K+channel SK3 has been described as one of the factors responsible for the progress of psychoneurological diseases, but the molecular basis of this is largely unknown. This report reveals through use of immunohistochemistry and computational tomography that long-term increased expression of the SK3 small-conductance calcium-activated potassium channel (SK3-T/T) in mice induces a notable bilateral reduction of the hippocampal area (more than 50 %). Histological analysis showed that SK3-T/T mice have cellular disarrangements and neuron discontinuities in the hippocampal formation CA1 and CA3 neuronal layer. SK3 overexpression resulted in cognitive loss as determined by the object recognition test. Electrophysiological examination of hippocampal slices revealed that SK3 channel overexpression induced deficiency of long-term potentiation in hippocampal microcircuits. In association with these results, there were changes at the mRNA levels of some genes involved in Alzheimer's disease and/or linked to schizophrenia, epilepsy, and autism. Taken together, these features suggest that augmenting the function of SK3 ion channel in mice may present a unique opportunity to investigate the neural basis of central nervous system dysfunctions associated with schizophrenia, Alzheimer's disease, or other neuropsychiatric/neurodegenerative disorders in this model system. As a more detailed understanding of the role of the SK3 channel in brain disorders is limited by the lack of specific SK3 antagonists and agonists, the results observed in this study are of significant interest; they suggest a new approach for the development of neuroprotective strategies in neuropsychiatric/neurodegenerative diseases with SK3 representing a potential drug target.
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Martin
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany.
authors.forename: Marcio
authors.initials: M
authors.lastname: Lazzarini
authors.affiliation: Department of Diagnostic and Interventional Radiology, Georg-August University Medical Center, 37075, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dullin
authors.affiliation: Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.|Department of Neuro- and Sensory Physiology, Georg-August University Medical Center, 37073, Göttingen, Germany.
authors.forename: Saju
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, 14040-900, Ribeirão Preto, Brazil.
authors.forename: Felipe V
authors.initials: FV
authors.lastname: Gomes
authors.affiliation: Department of Neurosurgery, Georg-August University Medical Center, 37075, Göttingen, Germany.
authors.forename: Milena
authors.initials: M
authors.lastname: Ninkovic
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany.|Bernstein Focus for Neurotechnology and Bernstein Center for Computational Neuroscience, Göttingen, Germany.|Theoretical Neurophysics, Department of Non-linear Dynamics, Max Planck Institute for Dynamics and Self-Organization, 37077, Göttingen, Germany.|The Interdisciplinary Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Hady
authors.affiliation: Oncophysiology Group, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pardo
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany. stuehmer@em.mpg.de.|Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. stuehmer@em.mpg.de.|Bernstein Focus for Neurotechnology and Bernstein Center for Computational Neuroscience, Göttingen, Germany. stuehmer@em.mpg.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Stühmer
authors.affiliation: Department of Morphology, Physiology and Pathology, CNPQ Research 1B (Biophysics, Biochemistry, Pharmacology and Neuroscience), University of São Paulo Dental School of Ribeirão Preto, Avenida do Café 3400, 14040-904, Ribeirão Preto, Brazil. eadelbel@forp.usp.br.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del-Bel
mesh_terms: D000818:Animals; D001284:Atrophy; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C496900:Kcnn3 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels
keywords: Alzheimer’s disease; Learning and memory; Potassium channel KCa2.3; Schizophrenia; Whole-cell patch clamp