“Sex hormones dependent modulation of thalamic inputs to striatal fast spiking interneurons”

Growing evidence suggests that many striatal-mediated behaviors and relevant disorders are sensitive to biological sex and estrous cycle-dependent changes in sex hormones (Meitzen et al., 2018). Though striatal-related behaviors and pathologies display clear sex dimorphism, the mechanisms by which sex and gonadal hormones influence striatal neurons´ physiology remain largely unknown (Meitzen et al., 2018). Most of the works have focused on medium-sized GABAergic spiny projection neurons (SPNs also referred to as ‘‘medium spiny neurons’’) (Burke et al., 2017). Besides the direct action on SPNs through membrane and/or nuclear receptors, sex hormones have been proposed to act also on striatal interneurons, which synapse on SPNs (Krentzel & Meitzen, 2018a), thus shaping striatal network activity and behavioral outcome (Barth et al., 2015; Meitzen, 2018; Krentzel., 2020; McArthur and Gillies, 2011; Chuhma et al., 2011). The relationship between striatal interneurons and sex hormones has been investigated only at the behavioral level (Krentzel & Meitzen, 2018), indicating that specific disruption of fast-spiking interneuron (FSI) sub population in mice dorsal striatum is sufficient to produce autism spectrum disorder and Tourette syndrome-like behavioral abnormalities and aberrant signaling in SPNs activity in males but not in females (Rapanelli et al., 2017). FSIs exert a crucial position in intrastriatal information processing of inputs that are conveyed to the striatum mainly from the cortex and thalamus (Hjorth et al., 2020). In this study, we combined ex vivo pharmacological and optogenetic approaches with fiber photometry to examine how sex and the estrous cycle influence FSI integration of thalamic inputs and intrinsic excitability. We found that FSIs responsiveness to thalamic inputs is affected by both sex and estrous cycle. Male FSIs showed a stronger integration of thalamic inputs compared to females, while in females, FSI interneuron thalamic input integration was affected by the estrous cycle stage. Thus, our investigation reveals evidence supporting a sex-dependent modulation of synaptic processing in striatal FSIs. Synaptic integration is a cellular process that underlies motor control and learning, therefore sex-dependent regulation of thalamic inputs on FSIs could have strong implications for striatal behavioral outputs. By further screening FSI physiology, we found that FSI intrinsic excitability was affected by sex and gonadal hormone levels throughout the estrous cycle. Manipulating estrogen-mediated signaling exacerbated the excitability differences observed indicating a possible estradiol role in modulating FSI ionic conductances. These findings identify modulation of the thalamus-FSI microcircuit as one of the possible substrates for sex differences in striatal-based behavior and psychomotor disorders caused by striatal dysfunction.