Characterization of developing striatal circuitry in early-onset dystonia

Introduction: Dystonia is a movement disorder characterized by involuntary twisting and sustained postures. Impaired torsinA function causes the neurodevelopmental disorder of early-onset dystonia (DYT-TOR1A). TorsinA is highly expressed during development, and its loss of function during neural maturation impacts circuit development, leading to abnormal movements. Motor symptoms can be improved by lesioning or stimulating the globus pallidus interna (GPi) or administering antimuscarinic medications, implicating basal ganglia and cholinergic neuron involvement.

Methods: We conditionally deleted Tor1a from forebrain GABAergic and cholinergic neurons (using Dlx5/6-Cre) to generate overtly symptomatic “Dlx-CKO” mice. Like the neurodevelopmental onset of human DYT-TOR1A, motor abnormalities in Dlx-CKO mice emerge during juvenile development. Electrophysiological alterations found in developing Dlx-CKO striata and cholinergic interneurons (ChIs) motivate our anatomical studies. Using immunohistochemistry, confocal imaging, and neuroanatomical analyses, we characterized striatal ChI morphology and connectivity during development and maturation, with or without cholinergic torsinA re-expression using a novel ChAT-IRES-Tor1a construct.

Results: We find that maturing ChIs in Dlx-CKO striata exhibit transient defects in neurite outgrowth and persistent alterations in afferent connectivity that coincide with the onset of abnormal motor behavior. TorsinA re-expression in developing ChIs supports neuronal survival and morphology and promotes proper physiological striatal connectivity.

Conclusions: TorsinA loss-of-function causes morphological and synaptic alterations to maturing ChIs, consistent with a contribution to abnormal motor behavior.