The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

Abstract

Thalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca 2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesized that genes regulated by Shox2's transcriptional activity may be important for physiological properties of TCNs. In this study, we used RNA sequencing on control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Quantitative PCR confirmed that expression of Hcn2, 4 and Cav3.1 genes were affected by Shox2 KO. Western blotting showed expression of the proteins for these channels was decreased in the thalamus, and electrophysiological recordings showed that Shox2 KO impacted the firing and synaptic properties of TCNs. Finally, behavioral studies revealed that Shox2 expression in TCNs play a role in somatosensory function and object recognition memory. Overall, these results reveal Shox2 as a transcription factor important for TCN firing properties and thalamic function. 1 Processing of sensory information is mediated by precise circuitry that senses stimuli in 2 the periphery and transforms the information through a network of synaptic connections to 3 ultimately allow perception and cognitive processing of the surrounding world. Rhythmic 4 oscillations of brain activity crucial to cognitive function emerge from neuronal network 5 interactions that consist of reciprocal connections between the thalamus, the inhibitory 6 thalamic reticular nucleus and the cortex 1 . Dysfunction of these oscillations caused by 7 aberrant activity in the thalamic circuit is thought to play a role in many neuropathological 8 conditions, including epilepsy 2-4 , autism 5-7 , and schizophrenia [8][9][10][11] . Furthermore, damage to 9 thalamic nuclei, especially medial and anterior nuclei, causes severe memory deficits known 10 as diencephalic amnesia 12-17 . 11 The intrinsic properties that shape action potential firing and contribute to rhythmic 12 oscillations of the thalamocortical neurons (TCNs) are important for efficient transfer of 13 information from the thalamus to the cortex. Notably, TCNs switch their firing states between 14 2 modes, burst and tonic fi...