Shox2 is necessary for normal thalamic spindle function

Abstract

The cellular identity of thalamocortical neurons (TCNs), namely their firing properties, dictates brain-wide activity patterns, such as sleep spindles. Transcription factors are critical to the determination of cellular identity. Previously, we discovered that a subset of TCNs express the transcription factor, Shox2, and, in a globalShox2KO, established that TCNs within the anterior nucleus of the thalamus rely on the expression ofShox2to regulate key ion channels that are necessary to maintain their firing properties. From this, we hypothesized thatShox2expression, through the regulation of firing properties of TCNs, is critical for the thalamocortical circuit to generate spindle oscillations. We exploited the somatosensory thalamocortical circuit to investigate this by creating a primary somatosensory thalamus (VB)Shox2knockdown mouse model. We delivered Cre into the VB of P21 Shox2fl/flmice using viral infection and comparedin vitro, patch-clamp recordings fromShox2+andShox2knockdown TCNs, finding thatShox2expression is indeed critical to maintain burst and tonic firing properties of VB TCNs. Since Shox2 is important developmentally and firing from TCNs to cortex during development structures the circuit, we performed ultrasound-guided P3 injections at P3 to generate an early-stage, Shox2 VB knockdown, but found no changes in the layer four, barrel map (VB cortical target). Despite this, Shox2 knockdown mice exhibit reduced sleep-spindle EEG density. Further, key behaviors associated with spindles and proper VB thalamic function—memory consolidation and somatosensory perception—are significantly impaired. These results indicate that the impact on spindle function is likely due to cell autonomous changes to TCNs rather than circuit changes, confirming our hypothesis thatShox2is necessary for normal thalamic spindle function and implicating a potential role forShox2in autism and schizophrenia pathologies.