Quantitative evaluation of hypothalamic gaba-ergic neurotransmission in major depression.

D.M. Krolewski; A. Medina; I.A. Kerman; S. Burke; W.E. Bunney; R.M. Myers; J.D. Barchas; A. Shatzberg; H. Akil; E.G. Jones; S.J. Watson
Society for Neuroscience. 2010.


The hypothalamus includes a number of anatomical nuclei that coordinate autonomic responses that are altered in psychiatric disorders including stress reactivity, feeding and sleeping patterns. These functions are directly controlled by neuronal intercommunication between local and extra-hypothalamic nuclei. Inhibitory gamma-aminobutyric acid (GABA) expressing neurons are present throughout the hypothalamus and are, therefore, key in regulating such processes. Previous research from the Pritzker Neuropsychiatric Research Consortium (Choudary et al., 2005) has shown alterations in genetic markers for GABA-ergic function in the frontal cortex of subjects diagnosed with major depressive disorder (MDD). The aim of the current study is to expand on these data by examining the relative degree of hypothalamic GABA-ergic neurotransmission in the same cohort of MDD subjects. To achieve this, we performed in situ hybridization on post-mortem hypothalamic tissue utilizing cRNA probes for the GABA synthesizing enzyme isoforms glutamate decarboxylase (GAD) 65 and 67. Subsequent quantitative analyses of GAD65 and GAD67 expression have enabled the present study to inspect the clinical relevance of these enzymes which are responsible for the transient and constitutive production of regional hypothalamic GABA, respectively. More specifically, a thorough evaluation of functionally distinct areas such as the paraventricular, periventricular, and ventromedial nuclei as well as the lateral hypothalamic area and mammillary bodies was employed. The results of this investigation on human hypothalamic GABA-ergic function will provide detailed insight to the neurogenetic underpinnings of psychiatric disorders.