Andrew Kobets

Date of Award

January 2012

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Christopher J. Pittenger

Subject Area(s)

Neurosciences

Abstract

Tourette syndrome is a complex neurodevelopmental disorder that causes significant morbidity for pediatric and adult patients and is present in up to 1% of the population. Genetic, functional and volumetric analyses suggest that the core neuropathology of Tourette syndrome resides within the dysfunctional cortico-striato-thalamo-cortical circuitry of the basal ganglia. Patients can have 5% smaller striatal volumes when compared to age-matched controls and up to 60% reductions in small populations of regulatory interneurons concurrent with severe clinical symptomatology. These interneurons are thought to regulate the immense cortical input that is fed into the striatum and modulate depolarization of neighboring medium spiny neurons as they form output to the globus pallidus. The goal of this work is to recapitulate interneuron loss in patients with severe tics and create an animal model for Tourette syndrome.

Our group combined the regional specificity of stereotactic plasmid delivery with the cell-type specificity of transgenic cre mice in order to induce the expression of diphtheria toxin receptor in only those striatal interneurons genetically engineered to express cre-recombinase. Recombination of a lox-flanked diphtheria toxin receptor gene will activate protein production only in these interneurons, inducing receptor expression and then selective apoptosis after systemic diphtheria toxin administration. This system allows the behavioral consequences of interneuron ablation to be studied aside from perioperative inflammation of virus injection and with the temporal control of distant intraperitoneal diphtheria toxin injection.

Pre-pulse inhibition is the ability to reduce the `startle' response to a stimulus of high amplitude when another stimulus of lower intensity is given immediately beforehand. It is a quantitative behavioral assay that is deficient in patients with Tourette syndrome and mice treated with high dose amphetamines. Its neurocircuitry is thought to be based in the syncytium of the striatal interneurons of the basal ganglia, and deficiencies of behavioral inhibition are thought to lie along the spectrum of sensorimotor-gating abnormalities inherent to Tourette syndrome.

We demonstrated consistent diphtheria toxin receptor expression specific to the acetylcholine-expressing interneurons of the striatum. After diphtheria toxin was administrated to a subset of mice two weeks post-operatively, a reduction in prepulse inhibition was seen as compared to the toxin-naive controls in the cohort. The ablation of these cells was confirmed via immunohistochemistry of the sectioned striatal tissue and the degree of interneuron loss appeared to correlate with behavioral alterations seen on prepulse testing over the course of 7 weeks.

Future goals of our work include: understanding the downstream neurochemical changes that may ensue from striatal interneuron loss, studying the compensatory mechanisms which may reverse symptomatology over time, assessing the validity of this model using medications classically used to treat symptoms in Tourette syndrome (typical and atypical antipsychotics, α2-agonists), and ultimately trialing novel therapeutics to better treat patients in the future.

Comments

This is an Open Access Thesis.

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