Ultrastructural localization of glutamate delta receptor 1 in the lateral habenula and central amygdala of mice and monkeys Restricted; Files & ToC

Abstract

The delta family of ionotropic glutamate receptors (GluDs) are atypical in that they do not bind glutamate nor do they display typical ligand-induced ionotropic activity. Instead, GluDs form trans-synaptic complexes that are crucial for the formation and maintenance of synapses. GluD1 has widespread brain expression, and accumulating evidence demonstrates that depending on the synapse type, activity, and location, GluD1 can exhibit diverse functions beyond synaptogenesis. A better understanding of GluD1’s potential role in a specific brain region requires a detailed map of its subcellular and subsynaptic localization. Thus, this dissertation utilizes immuno-electron microscopy methods to investigate the ultrastructural localization of GluD1 in two previously unexplored regions: the lateral habenula (LHb) and the central amygdala (CeA). 

In the LHb, GluD1 immunoreactivity was primarily expressed in dendritic profiles, with lower expression in somata, spines, and glia. We observed strong GluD1 expression in the core of symmetric GABAergic synapses, suggesting GluD1 may be associated with inhibitory transmission in the LHb. Less frequently, GluD1 was also found at the edges of asymmetric, putative glutamatergic, synapses. A combination of anterograde tracing and immunogold labeling studies showed that a significant proportion of lateral hypothalamus and entopeduncular nucleus afferents express postsynaptic GluD1 localization in the rat LHb. 

Through the spino-parabrachio-amygdaloid pain pathway, the lateral capsular subdivisions of the CeA (CeLC) receives direct inputs from calcitonin gene-related peptide (CGRP)-containing parabrachial (PB) neurons. Our immunolabeling studies demonstrate that CGRP+ terminals form symmetric and asymmetric synapses with dendrites, symmetric synapses with soma, and asymmetric synapses with spines in the CeLC. Most CGRP+ terminals forming symmetric synapses expressed vGluT2 immunoreactivity and none were immunoreactive for GABA. GluD1 was expressed in the core of symmetric axo-dendritic and axo-somatic synapses and peri-synaptic to asymmetric synapses formed by PB-CGRP+ terminals. These results show that the CGRP+PB-CeLC projection mediates its effects through a heterogenous population of terminals that display strong synaptic relationships with GluD1.

Altogether, these findings provide a comprehensive analysis of the subsynaptic localization of GluD1 in the rodent and primate LHb and CeA, establishing a strong foundation for future functional, behavioral, and pharmacological studies investigating the role of GluD1 in the mammalian brain.

Table of Contents

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About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Health Sciences, Pharmacology
Stichwort	Electron Microscopy Immunocytochemistry Central Amygdala Lateral Habenula glutamate delta receptor
Committee Chair / Thesis Advisor	Yoland Smith, Emory University
Committee Members	Ellen Hess, Emory University Shashank M. Dravid, Texas A&M University J. Paul Bolam, University of Oxford Shannon L. Gourley, Emory University

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