Synaptic GABA dysfunction of thalamocortical neurons impairs sleep spindle morphology and recovery from fearful memories

Abstract Sleep spindles are rhythmic electroencephalographic signatures of non-rapid-eye-movement sleep. Their dysregulation has been implicated in several neuropsychiatric illnesses. Spindles have a characteristic waxing and waning shape, but the cellular and circuit mechanisms controlling their shape are not well understood. Recent but sparse research has implied that sleep spindle shape becomes abnormal in post-traumatic stress disorder (PTSD). PTSD patients have dysfunctional GABA A receptors in midline thalamic regions, areas involved in the orchestration of sleep spindles. We modelled this GABA A dysfunction within thalamocortical (TC) neurons using localized CRISPR-Cas9 technology to test the hypothesis that GABA dysfunction would dysregulate sleep spindle shape and cause symptoms of PTSD, in mouse model behavioral evaluations. We found sleep spindles were shorter and abnormally shaped, having lost their characteristic waxing and waning shape, in mice with GABA A receptor knock-down in TC neurons (TC-α1KD). TC-α1KD mice failed to recover from learned fearful reactions following an aversive stimulus. We tested this with a contextual fear conditioning paradigm using electric foot shocks. A control group with intact GABA A receptors successfully habituated to the fear conditioned location in subsequent visits to that context without foot shocks. In contrast, TC-α1KD mice never habituated, suggesting abnormally extended fearful memories. The number of inhibitory post synaptic currents in TC neurons were significantly decreased in vitro , confirming an effective knock-down. Our results imply that abnormally shaped sleep spindles may serve as a biomarker of GABA A receptor dysfunction in TC neurons which may be involved in abnormal fear processing in PTSD. We postulate GABA A receptor dysfunction in TC neurons may be underlying pathophysiology of PTSD and our findings here may inspire the development of screens, diagnostics and objective characteristics of stress related disorders, including PTSD.