The role of Shox2 in thalamic development and function

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The thalamus is a brain area that is critical for sensory, motor, and cognitive processing as it is located centrally within the brain and connects extensively with cortical and subcortical areas. Aberrant thalamic function is implicated in pathological conditions such as epilepsy, autism, and schizophrenia, but the specific mechanisms of the thalamic disruptions are poorly understood. The thalamus is highly organized into nuclei that send outputs to and receive inputs from specific cortical areas. The neurons of the thalamus entrain oscillatory activity that is important for sleep and conscious state. These neurons express ion channels and receive synaptic inputs that are important for these characteristic firing patterns that generate slow synchronized oscillations. Understanding the mechanisms that lay the foundations for expression of the channels that mediate these rhythms and can be aberrantly regulated in developmental mental health disorders is important to ultimately prevent and develop therapeutic interventions for these disorders. The transcription factor, Shox2, represents a possible mechanism to control expression of several ion channel genes important for oscillatory activity. The short stature homeobox-containing gene (hSHOX) is a homeobox gene that is an important factor that is required for limb development. SHOX is present on the telomeric pseudoautosomal region 1 at the distal end of the X and Y chromosomes. SHOX haploinsufficiency causes Léri-Weill dyschondrosteosis and Turner Syndrome, which result shortened and malformed limbs. The mouse homologue, mShox2, is closely related to the SHOX gene and plays a role in the development of proximal limbs, palate, heart, dorsal root ganglia neurons, and interneurons of the spinal cord. Despite high levels of expression in the central nervous system, the role of Shox2 in the development of the nervous system is essentially unknown. Our preliminary data suggest that Shox2 is highly expressed in the diencephalon, particularly nuclei within the dorsal thalamus, and that Shox2 expression plays a functional role in the mature thalamus, suppressing pharmacologically-induced seizures. Furthermore, Shox2 is important for expression of mRNAs for several channel subunits that are important for oscillatory activity. Understanding the role of Shox2 in brain development is imperative to determine mechanisms underlying developmental disorders. The central hypothesis of this project is that Shox2 is an important transcription factor that controls the function of thalamic relay neurons. We will take advantage of cutting-edge transgenic mouse models and combine multi-level analysis, including behavior, genetic molecular, and electrophysiological studies to determine: 1) the role of Shox2 expression in seizure intensity and 2) the role of Shox2 in oscillatory behavior of thalamic neurons. These aims will enhance our understanding of thalamic development and will lay the groundwork for future studies investigating possible mechanisms and genetic targets that are dysregulated in developmental disorders.