D1 and D5 dopamine receptor signaling inarea 9 of the Macaca mulatta dorsolateral prefrontalcortex Pubblico

Abstract

Schizophrenia is a debilitating disorder that is characterized by impairments in perception, thinking, social functioning and cognition. It is cognitive ability which is the best predictor of employment, social integration and relapse. Working memory (WM) is a core cognitive process that is severely impaired in schizophrenia, and WM depends on intact circuitry and dopaminergic signaling via the D1 family of dopamine receptors (D1R) in the dorsolateral prefrontal cortex (dlPFC). D1R activation and WM performance have an inverted-U relationship, such that too much or too little D1R stimulation results in poor WM performance. It was the goal of my experiments to contribute to understanding what underlies this dose-dependent relationship.

Of the two D1R subtypes, D1 and D5, the D5 receptor has a 10-fold higher affinity for dopamine. The circuitry of the PFC includes excitatory spiny pyramidal cells, and inhibitory interneurons which can be defined by the presence of calcium-binding proteins like parvalbumin (PV) and calretinin (CR). I demonstrate that D1 and D5 are co-localized on pyramidal cell spines but not on interneurons. PV interneurons predominately express D1, while CR interneurons predominately express D5. The D1R activate a complex signal transduction pathway that includes inhibitor-1 (I-1), DARPP-32, protein phosphatase 1 (PP1) and PP11. The precise localization of these proteins is critical for D1R signaling. I demonstrate that I-1 and DARPP-32 are infrequently identified in pyramidal cell spines, and that the signaling environments in PV and CR interneurons differ from each other and from pyramidal cell spines. The implications these different signaling environments may have on D1R signaling in the PFC are discussed.

Table of Contents

Chapter 1: General Introduction

Clinical features of schizophrenia................................................ 1-4

Working memory and schizophrenia............................................. 4-5

Circuitry of the dorsolateral prefrontal cortex................................... 5-8

The cellular correlate of working memory.............................. 6-8

Dopamine and working memory.................................................. 8-11

Dopamine receptors and working memory............................. 8-10

D1R stimulation and delay cells......................................... 10-11

D1 and D5 in dorsolateral prefrontal cortical circuitry......................... 11-15

Inhibitor-1 and DARPP-32............................................... 12-13

Protein phosphatase 1..................................................... 13-15

Chapter 2: Localization of D1 and D5 in the neuropil of Macaca mulatta prefrontal cortical area 9

Introduction........................................................................... 21-22

Methods................................................................................ 22-30

Antisera....................................................................... 22-23

Western blotting.............................................................. 23-24

Animals and preparation of tissue for immunohistochemistry......... 24

Single-label immunohistochemistry....................................... 24-25

Double-label immunogold/DAB immunohistochemistry.............. 25-26

Double-label cocktail........................................................ 26-27

Analysis of material......................................................... 27-30

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Parola chiave	Electron Microscopy Prefrontal Cortex Signal Transduction Working Memory Dopamine
Committee Chair / Thesis Advisor	Muly, E Christopher, Emory University
Committee Members	Rainnie, Donald, Emory University Hall, Randy A, Emory University Smith, Yoland, Emory University Li, Lian, Emory University

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