Abstract/Details

Regulation of striatal medium spiny neuron GABAA receptor mediated tonic current


2010 2010

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Abstract (summary)

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 β3 subunit largely regulates tonic current based on phosphorylation state and dopamine receptor activation. Thus, D2+ MSNs express tonic current through a basally phosphorylated β3 subunit, while under proper conditions where the β3 subunit becomes phosphorylated, D1+ MSNs also express tonic current. Indeed, a transgenic mouse with β3 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.

Indexing (details)


Subject
Pharmacology
Classification
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; GABA receptor; Striatum; Tonic current
Title
Regulation of striatal medium spiny neuron GABAA receptor mediated tonic current
Author
Janssen Schroeder, Megan J.
Number of pages
212
Publication year
2010
Degree date
2010
School code
0076
Source
DAI-B 71/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124090061
Advisor
Vicini, Stefano
Committee member
Ahern, Gerard; Huntsman, Molly; Lovinger, David; Wolfe, Barry
University/institution
Georgetown University
Department
Pharmacology
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3412029
ProQuest document ID
737511124
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/737511124/abstract
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