STEALTHY VULNERABILITIES: ATYPICAL POSTNATAL DEVELOPMENT OF THE STRIATAL CONNECTOME IN A MOUSE MODEL OF HUNTINGTON’S DISEASE

Huntington’s disease (HD) is an incurable dominant neurodegenerative disorder caused by an abnormal expansion of the CAG tract in the coding region of the huntingtin (HTT) gene. Patients carrying the mutant huntingtin (mHTT) protein share several neurological impairments defined by a triad of slow-progressing motor, cognitive and psychiatric symptoms. HD is characterized by the dysfunction and death of cortical and striatal neurons. Although symptoms do not typically manifest until the adulthood, recent studies show evidence that abnormal neurodevelopment contributes to HD pathophysiology. Nevertheless, the specific processes partaking in the assembly/refinement of the striatal networks in HD remain understudied. We investigate HD-associated alterations in the postnatal development of the emerging striatal circuits and functional hubs using a multidisciplinary approach. We observe a transient increase in the abundance of maturing indirect medium spiny neurons (iMSN) which contributes to an early shift in the subpopulation composition of the striatum. Furthermore, the tracing of output projections of MSN neurons shows abnormal formation of both striatopallidal (indirect) and striatonigral (direct) pathways suggesting developmental alterations in axonal growth and/or stabilization. Additionally, retrograde rabies virus tracing demonstrates subpopulation-specific changes in the corticostriatal synaptic wiring during postnatal maturation. In conclusion, here we show that mHTT profoundly affects different steps of the striatal development including the specification/differentiation of MSNs and the formation of mesoscale connections during early postnatal stages. The exact contribution of these neurodevelopmental anomalies to the disease progression remains to be established. Early therapeutical interventions targeting these defects could potentially delay and ameliorate the adult pathology.