Subtype-specific alterations in first- and higher-order thalamic reticular neurons in the Shank3 mutant mouse model of autism

The thalamic reticular nucleus (TRN) is a critical inhibitory structure in the thalamocortical network, playing key roles in sensory processing, attention, cognitive flexibility, and sleep rhythms; importantly these functions are altered in autism spectrum disorder (ASD). The TRN consists mainly of two neuronal subpopulations: first order (FO) neurons, which modulate sensory relay nuclei, and higher-order (HO) neurons, which control associative thalamic circuits. TRN-FO neurons are located in the core region, show a high expression of repetitive burst firing, and are known to contribute to slow-wave oscillations. In contrast, neurons innervating HO thalamic nuclei are in the anterior and peripheral regions of the TRN and have fewer burst firing. These subpopulations provide specialized inhibition to thalamus, but their alterations in ASD have rarely been explored. We evaluated the reticular inhibitory system in thalamic nuclei (FO and HO) in Shank3 KO mice, a well-established monogenic model of ASD. We analyzed electrophysiological properties of targeted TRN neurons, our results show that TRN neurons projecting to FO and HO nuclei exhibit differential changes in Shank3 KO mice, including decreased burst firing in FO projecting neurons, which is crucial for maintaining sleep architecture. Additionally, we examined spontaneous and miniature inhibitory postsynaptic currents (IPSCs), in ventroposteromedial (VPM-FO) and posteromedial (POm-HO) thalamic nuclei. We show a reduction in frequency of spontaneous IPSCs and mIPSCs in VPM and POm. Together, our results show distinct alterations in the inhibitory control of FO and HO thalamic nuclei in Shank3 KO mice, which could contribute to the deficits in sleep and sensory processing observed in ASD.