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      Mechanisms of increased hippocampal excitability in the Mashl +/− mouse model of Na+ /K+ -ATPase dysfunction

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          Abstract

          Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable.

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          Interneurons of the hippocampus.

          T Freund, G Buzsáki (1996)
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            Autistic behavior in Scn1a+/− mice and rescue by enhanced GABAergic transmission

            Chang Sung Han, Chao Tai, Ruth Westenbroek … (2012)
            Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel NaV1.1 causes Dravet Syndrome (DS), a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviors in DS are poorly understood. Here we show that mice with Scn1a haploinsufficiency display hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a +/− mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of NaV1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviors and deficits in fear memory in DS mice, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for NaV1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviors in DS.
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              Highly energized inhibitory interneurons are a central element for information processing in cortical networks.

              Andreas Draguhn, Oliver Kann, Ismini Papageorgiou (2014)
              Gamma oscillations (∼30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.
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                Author and article information

                Journal
                Title: Epilepsia
                Abbreviated Title: Epilepsia
                Publisher: Wiley
                ISSN: 00139580
                Publication date Created: July 2018
                Publication date (Print): July 2018
                Publication date (Electronic): June 11 2018
                Volume: 59
                Issue: 7
                Pages: 1455-1468
                Affiliations
                [1 ]Division of Pediatric Neurology; Department of Pediatrics; Duke University Medical Center; Durham NC USA
                [2 ]Department of Neurobiology; Duke University School of Medicine; Durham NC USA
                [3 ]Durham Veterans Affairs Medical Center; Durham NC USA
                [4 ]Department of Psychiatry and Behavioral Sciences; Duke University Medical Center; Durham NC USA
                [5 ]Veterans Affairs Mid-Atlantic Region Mental Illness Research, Education, and Clinical Center; Durham NC USA
                [6 ]Department of Pharmacology and Cancer Biology; Duke University Medical Center; Durham NC USA
                Article
                DOI: 10.1111/epi.14441
                PubMed ID: 29889309
                SO-VID: 1bc5e185-ae11-4caf-8cd6-cbd8cbc854ab
                Copyright © © 2018
                License:

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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