Regulation of striatal medium spiny neuron GABAA receptor mediated tonic current.

摘要

The majority of striatal neurons are GABAergic projecting medium spiny neurons (MSNs), of which there are two types based on their primary axonal projection pathway and dopamine receptor expression. MSNs that express the dopamine D2 receptor (D2+) inhibit the globus pallidus to inhibit movement, while those that express the dopamine D1 receptor (D1+) inhibit the substantia nigra to facilitate movement. Although these neurons are morphologically and electrophysiologically indistinguishable, D2+ MSNs express greater GABAergic inhibitory tonic currents than D1+ MSNs in young mice.;In this thesis, I identify putative GABAA receptor subunits that underlie tonic current in striatal MSNs. Using whole-cell recordings in acute mouse brain slices from bacterial artificial chromosome transgenic mice where EGFP is driven by the Drd2 promoter and tdTomato protein is driven by the Drd1a promoter, I show that the GABAA receptor beta3 subunit largely regulates tonic current based on phosphorylation state and dopamine receptor activation. Thus, D2+ MSNs express tonic current through a basally phosphorylated beta3 subunit, while under proper conditions where the beta3 subunit becomes phosphorylated, D1+ MSNs also express tonic current. Indeed, a transgenic mouse with beta3 subunits selectively knocked-out of D2+ MSNs failed to demonstrate the typical tonic current pattern seen in wild type mice, suggesting that this subunit is particularly important in mediating tonic current.;In this thesis, I also compare striatal MSNs to a subtype of striatal GABAergic interneurons that express Neuropeptide Y (NPY +). These neurons have a characteristic cell-attached firing pattern, making them a likely source for the ambient GABA necessary for MSN tonic currents. My data suggest that these interneurons receive fewer inhibitory inputs with different presynaptic origins than MSNs.;My thesis work has revealed important players in striatal tonic current and such insight offers innumerable pharmacological targets in the treatment of Parkinson's disease, and other striatally relevant diseases, where an imbalance in the D2+ and D1+ MSN projection pathways causes symptomatic akinetic behaviors.