NSC PhD Thesis Proposal: Evan McConnell

The Role of Astrocytes in Noradrenaline Mediated Attenuation of Motor Tics

Monday, March 10

11:00 AM12:00 PM MC 3-6408 (K-307)

Professor Maiken Nedergaard, M.D., D.M.Sc.

Abstract:

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the presence of at least one motor and one vocal tic for a minimum of one year. Its prevalence is estimated at roughly 1-4% of the general population in North and South America as well as Europe and Asia. While a variety of neurotransmitters and neuromodulators have been linked to the pathophysiology and treatment of TS, namely dopamine, another catecholamine, norepinephrine may be playing a larger role than previously thought. The evidence for the role of norepinephrine (NE) in TS is as follows: (1) Guanfacine and clonidine, two α2-adrenergic agonists are currently considered first-line therapy for patients with TS. (2) The severity of motor tics in TS is strongly affected by adrenergic-sympathetic changes associated with stressful situations (i.e. birthday parties, test-taking). (3) NE was found to be 55% higher in TS patients’ cerebrospinal fluid compared with controls. (4) Patients with TS tic much more when they are at rest than when they are engaged in a task requiring proper executive function. While TS has largely been thought to be the sole purview of neurons, astrocytes, which respond robustly to NE derived from the locus coerulues (LC), may also be playing a larger role than previously thought. Several recent papers from our lab link astrocytes as downstream effectors of the LC resulting in uptake of extracellular potassium and inhibition of juxtaposed excitatory neurons.

We hypothesize astrocytes play a key role in suppressing motor tics by exerting dynamic regulation of extracellular potassium as a function of receptor mediated noradrenergic stimulation. To test this we will make use of a recently developed mouse model of motor tics involving infusion of bicuculline, a GABAA antagonist into the striatum resulting in disinhibition of downstream thalamocortical circuitry involved in motor execution. We will combine this motor tic model with optogenetic manipulation of the LC in Tyrosine Hydroxylase::cre mice using a stereotaxically delivered virus containing channelrhodopsin2 or halorhodopsin to stimulate or inhibit the LC respectively. Optogenetics will provide a powerful tool to selectively modulate the noradrenergic system in an a highly temporally controlled manner which when combined with the striatal disinhibition motor tic model will allow us to investigate the role of NE in motor tics. This work will potentially provide new insight into the role of astrocytes in the NE-LC system, cortical network modulation and motor tic suppression.