Synaptic GABA dysfunction of thalamocortical neurons impairs sleep spindle morphology and fear extinction.

Abstract

The neural mechanisms which control the characteristic waxing and waning shape of sleep spindles and their dysregulation in neuropsychiatric illnesses are unresolved. Recent, sparse research shows post-traumatic stress disorder (PTSD) presents with abnormal spindle morphology and dysfunctional synaptic GABAA receptors in midline thalamic regions. We modeled this GABAA receptor dysfunction by localized CRISPR-Cas9-knockdown in mice. In contrast to a control group with intact GABAA receptors, mice with synaptic GABAA receptor knock-down in thalamocortical (TC) neurons lost the characteristic waxing and waning shape of sleep spindles and exhibited a failure to diminish conditioned contextual fear responses. Our results suggest that abnormally shaped sleep spindles may be a marker of synaptic GABA dysfunction in TC neurons and an indicator of disrupted fear extinction.