Targeting the NMDA receptor-mediated disruption of autonomous subthalamic nucleus activity to ameliorate physiological and motor symptoms in a mouse model of Parkinson's Disease

Northwestern University At Chicago, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): The degeneration of substantia nigra dopamine neurons drives the core motor symptoms of idiopathic and experimental Parkinson's disease (PD) by profoundly altering the frequency and pattern of activity in the cortico-basal ganglia-thalamo-cortical loop. The classical rate model of basal ganglia dysfunction suggests that loss of dopamine results in an increase in the activity of the indirect (movement-inhibiting) pathway relative to the activity of the direct (movement-promoting) pathway. However, therapeutic interventions such as L-DOPA and deep brain stimulation (DBS) of the subthalamic nucleus (STN) do not alter firing rates in a manner that is consistent with the rate model. Instead, the amelioration of motor symptoms in experimental and idiopathic PD is more closely related to reductions in abnormal, persistent, synchronous, band (13-30Hz) activity. However, the causes of abnormal-band activity in PD remain poorly defined. We have found that the autonomous activity of the STN, which is a component of the indirect and hyperdirect pathways, is lost in the unilateral 6-hydroxydopamine (6- OHDA) lesion model of PD. Loss of activity appears to be through NMDA receptor (R)-mediated upregulation of an ATP-dependent potassium (KATP) channel conductance that hyperpolarizes STN neurons. Loss of decorrelating autonomous STN activity may increase cortical patterning of the STN and thus contribute to the amplification and persistence of band activity in PD and its models. The proposed project will therefore investigate the mechanisms underlying the disruption of autonomous STN activity and determine whether the rescue of intrinsic STN excitability is therapeutic in experimental PD. Using a combination of viral vector-mediated genetic manipulations, electrophysiological recording ex vivo and in vivo and motor behavioral testing in the 6-OHDA mouse model of PD, 3 Specific Aims will be addressed. The applicant will determine: 1) whether knockdown of STN NMDA receptors in vivo prevents loss of autonomous STN activity, and the NMDAR-linked signaling pathways that upregulate STN KATP channels; 2) whether knockdown of STN NMDARs normalizes cortico-basal ganglia-thalamo- cortical loop activity and ameliorates motor dysfunction; and 3) whether restoration of intrinsic STN activity through expression and activation of designer receptors exclusively activated by designer drugs (DREADDs) normalizes cortico-basal ganglia-thalamo-cortical loop activity and ameliorates motor dysfunction. Through the proposed training plan the applicant will gain expertise in molecular, electrophysiological, anatomical and behavioral techniques and develop the analytical and communication skills necessary to achieve her goal of becoming an independent neuroscientist focused on disease mechanisms and therapeutics.