Modulation of striatal cholinergic interneuron activity to prevent dystonic cerebral palsy

PROJECT SUMMARY
This proposal will determine whether increasing striatal cholinergic interneuron (ChI) activity in the developing
mouse brain can prevent dystonia following neonatal brain injury
. Dystonic cerebral palsy (CP) due to neonatal
brain injury is the most common cause of childhood dystonia and is often medically refractory and functionally
debilitating. Yet, its unique pathophysiology remains understudied. Dystonia pathophysiology is more commonly
studied in models of rare genetic dystonias which are characterized by striatal ChI hyperexcitability. However,
anticholinergic medications are often ineffective for treating dystonia in CP. Determining whether there is striatal
cholinergic pathology specific to dystonic CP could yield better targeted treatments. To this end, I have developed
a clinically-relevant rodent model of neonatal hypoxic brain injury that displays electrophysiologic markers of
dystonia three weeks after injury, mimicking the clinical latency period between neonatal brain injury and dystonia
emergence. This latency period allows testing of pre-symptomatic interventions for dystonia prevention. My
preliminary data demonstrate increased striatal ChI number in my model but that striatal ChI excitation in young
mice during the pre-symptomatic window may be protective against dystonia. In sum, these data suggest that
increased striatal ChI number and striatal ChI hyperexcitability may be compensatory mechanisms that are
protective against dystonia and, therefore, could be enhanced to prevent dystonia following neonatal brain injury.
To test this hypothesis, I propose the following aims: (1) determine whether chemogenetic modulation of striatal
ChI activity in young mice after neonatal brain injury changes dystonia severity in adult mice; (2) determine
whether chemogenetic modulation of striatal ChI activity in young, otherwise healthy, mice can cause dystonia
in adult mice; and (3) determine whether the striatal ChI hyperexcitability observed in genetic dystonias is also
present in my model of dystonia following neonatal brain injury. These studies will determine whether pre-
symptomatically increasing striatal ChI firing after neonatal brain injury could reduce or prevent dystonia.
My long-term career goal is to run a translational research lab focused on preventative treatment development
for dystonic CP. I have studied basal ganglia pathophysiology for ten years and have developed a new model of
dystonia following neonatal brain injury which will be used for the proposed experiments. However, to complete
the proposed research and facilitate my transition to independence, I need additional mentored training in slice
electrophysiology (Dr. Steve Mennerick) and chemogenetics (Dr. Jordan McCall). As my physician-scientist
advisor, Dr. Joel Perlmutter will provide expertise in dystonia pathophysiology and ensure the translational
relevance of my research. The Washington University School of Medicine and Department of Neurology provide
a world-renowned research environment and a legacy of passionately and effectively supporting junior faculty.
In sum, my proposed research, mentorship team, training plan, and institutional environment pave my path to
independence and submission of an R01 on
identification of treatment targets
for dystonic CP.

Grant Number: 5K08NS117850-05
NIH Institute/Center: NIH
Principal Investigator: BHOOMA ARAVAMUTHAN