The Contribution of Tonic Inhibition to Cognitive Deficits in a Mouse Model of Bipolar Disease

Abstract

Introduction: Bipolar Type I is a neurological disorder characterized by manic episodes, hyperactivity, and cognitive deficits. A prevalent feature of this disorder is comorbid sleep disorders. In fact, sleep deprivation has been used to induce a bipolar phenotype in rodent models, through mechanisms not well understood. One possible mechanism is increased tonic inhibition in the hippocampus, a region critical for memory. Tonic inhibition in this region is mediated primarily by γ-aminobutyric acid type A receptors containing the α5 subunit, which regulate neuronal excitability, synaptic plasticity, and memory. Interestingly, tonic inhibition mediated by these receptors is increased in response to sleep disturbances. Therefore, this study aims to 1) determine whether tonic inhibition is increased in bipolar model mice, 2) determine whether increased tonic inhibition contributes to cognitive deficits in bipolar model mice, and 3) determine whether increased tonic inhibition contributes to hyperlocomotion in these mice.

Methods: To model bipolar disorder, mice are sleep deprived using the disk-over-water method. Tonic inhibition in the hippocampus will be bidirectionally manipulated: genetic overexpression will be used to increase inhibition, and optogenetic modifications will be used to reduce inhibition. The altering of tonic inhibition will also be conducted within the sleep deprived mice. These groups will be compared, along with control C57BL/6 mice regarding 1) level of tonic inhibition, using whole-cell voltage clamp recordings, 2) cognition, using the Morris water Y-maze, and 3) manic activity, using a locomotion assay.

Results: Sleep-deprived mice will exhibit increased tonic inhibition, impaired cognition, and hyperlocomotion. Decreasing tonic inhibition in sleep-deprived mice will rescue cognitive function. Conversely, increasing tonic inhibition in non-sleep-deprived mice will induce cognitive deficits similar to sleep-deprived mice. Altering tonic inhibition in the hippocampus will not affect locomotion.

Discussion: By comparing performance between groups using t-tests and ANOVAs, this study shows a potential mechanism underlying cognitive deficits in the sleep-deprivation model of bipolar disorder.

Conclusion: Tonic inhibition is a new pathway to consider for treatments and understanding the mechanisms behind Bipolar Type I.