In vivo optogenetic inhibition of striatal parvalbumin‐reactive interneurons induced genotype‐specific changes in neuronal activity without dystonic signs in male DYT1 knock‐in mice

Abstract

The pathophysiology of early‐onset torsion dystonia (TOR1A/DYT1) remains unclear. Like 70% of human mutation carriers, rodent models with ΔGAG mutation such as DYT1 knock‐in (KI) mice do not show overt dystonia but have subtle sensorimotor deficits and pattern of abnormal synaptic plasticity within the striatal microcircuits. There is evidence that dysfunction of striatal parvalbumin‐reactive (Parv+) fast‐spiking interneurons (FSIs) can be involved in dystonic signs. To elucidate the relevance of these GABAergic interneurons in the pathophysiology of DYT1 dystonia, we used in vivo optogenetics to specifically inhibit Parv+ and to detect changes in motor behavior and neuronal activity. Optogenetic fibers were bilaterally implanted into the dorsal striatum of male DYT1 KI mice and wild‐type (WT) littermates expressing halorhodopsin (eNpHR3.0) in Parv+ interneurons. While stimulations with yellow light pulses for up to 60 min at different pulse durations and interval lengths did not induce abnormal movements, such as dystonic signs, immunohistochemical examinations revealed genotype‐dependent differences. In contrast to WT mice, stimulated DYT1 KI showed decreased striatal neuronal activity, that is, less c‐Fos reactive neurons, and increased activation of cholinergic interneurons after optogenetic inhibition of Parv+ interneurons. These findings suggest an involvement of Parv+ interneurons in an impaired striatal network in DYT1 KI mice, but at least short‐term inhibition of these GABAergic interneurons is not sufficient to trigger a dystonic phenotype, similar to previously shown optogenetic activation of cholinergic interneurons.

Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model

“…These proteins are highly regulated which can be impacted by disease processes as shown by us and others. 54 , 114 , 115 Further recent studies corroborate this notion, for instance Frere et al. (2022) reported region-specific alterations in metabolism, synaptic signaling, and plasticity in hamster brains after SARS-CoV-2 infection, suggesting a disrupted brain homeostasis.…”

“…Parv and Calret are Calcium-binding proteins that are specific markers but also relevant to neuronal function. 41 , 54 , 55 …”

Striatal cholinergic interneuron development in models of DYT1 dystonia

“…Standardizing experimental readouts and testing various ages can help, but the lack of reproducibility also stems from the biological and technical requirements of different genetic models and an unclear understanding of torsinA mutations in cholinergic neurons. For example, some studies suggest that striatal cholinergic excitation alone is not sufficient to elicit dystonia-like behaviors [137,138], but the duration of striatal cholinergic excitation may be imperative for behavioral manifestation [52]. As for our understanding of pathogenic torsinA mutations, they are hypothesized to result in a loss-of-function or dominantnegative effect.…”

Unraveling dystonia circuitry in rodent models using novel neuromodulation techniques

“…In the dt sz hamster model of paroxysmal dystonia, a delayed maturation of parvalbumin-positive interneurons coincides with an agedependent development of a dystonia-like phenotype and abnormal basal ganglia output [52]. However, although selectively inhibiting striatal parvalbumin-positive interneurons led to a hyperactivation of cholinergic interneurons in DYT-TOR1A knock-in mice compared to wildtype controls, this manipulation failed to induce any behavioral changes, particularly dystonia [53]. Interestingly, optogenetic activation of the striatal D1 medium spiny neurons triggered dyskinesias in 6-OHDA mice [54].…”