Auditory Processing Deficits in MSH2-KO mice are linked to Aberrant Inhibitory Neuron Function in the Thalamic Reticular Nucleus

<p>DNA repair mechanisms are crucial for both cellular development and function. One highly conserved DNA repair factor is Mut-S Homolog 2 (<em>Msh2</em>), which corrects base-base mismatches and insertion/deletion loops. In humans, defects in this repair pathway are linked to diseases that have severe neurological pathologies. These include Lynch syndrome, Huntington’s disease and demyelination of the corpus callosum. The fundamental role of <em>Msh2</em> in brain function is unknown. Using an <em>Msh2^-/</em>^- mouse model we began an exploration of its impact on the processing of sensory information, a crucial function to an animal’s survival. The goal of this study was to investigate potential deficits in thalamo-cortical function. Using sound stimulation and immunohistochemical detection of active neurons with the immediate early gene cfos, we observed a significant decrease in cortical and thalamic cfos expression in <em>Msh2^-/</em>^- mice, indicating a reduction in neural activity compared to WT littermates. To examine possible mechanisms underlying this hypoactivity, we focused on the thalamic reticular nucleus (TRN): a critical regulator of corticothalamic and thalamocortical activity. We observed an increase in parvalbumin (PV⁺) expression, density, and cell area in the TRN, as well as high aggregation of the gap junction protein connexin-36 (Cx36). Cx36 is required for electrical coupling between TRN neurons, regulating the degree of synchrony in firing patterns. This indicates that Cx36- expressing PV⁺ cells in the TRN undergo increased gap junction coupling, thus leading to dysfunction in the electrical properties of the TRN, and thalamo-cortical sensory transmission. These findings suggest that <em>Msh2</em>, and therefore mismatch-repair, plays a role in the regulation or development of inhibitory interneurons in the TRN, leading to a downstream decrease of sound evoked neural activity.</p>

Name thesis:degree_name

Master of Science (M.S.)

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Biology

Year dc:date.available

2023

Author dc:creator

• Rahman, Sadia N

Contributors dc:contributor

• Hysell V. Oviedo
• Mark Emerson
• Pinar Ayata

• mismatch repair
• parvalbumin
• connexin36
• neural circuitry
• primary auditory cortex
• Cell and Developmental Biology

Repository record dc:identifier

https://academicworks.cuny.edu/cc_etds_theses/1113

OAI identifier oai:identifier

oai:academicworks.cuny.edu:cc_etds_theses-2157