Depression is a devastating neurobiological illness that affects 12-17% of the population often resulting in a debilitating quality of life and even suicide in many cases. Despite significant advances in the neurobiology and neuropharmacology of antidepressants, the molecular mechanisms underlying the actions of antidepressant treatment (ADT) have not been identified. Delay in the therapeutic effects of ADT coincides with changes in gene expression in intracellular pathways, and it is thought that these changes mediate the therapeutic effects of antidepressants. Recent studies have shown that chronic ADT alters gene expression, interestingly, components of various growth factor signaling cascades. This is of particular significance as growth factors play a central role in neurogenesis, which has recently been shown as a necessary for the behavioral response of ADT. In contrast, stress downregulates growth factor signaling and reduces levels of neurogenesis. Emerging interactions between growth factors, ADT, stress and neurogenesis indicate that examining growth factor regulation in the brain warrants further attention. Given that the choroid plexus (CP) is a major production site for various growth factor mRNAs and protein in the brain, it is worthwhile to examine their regulation in response to ADT and behavioral stress models.
The aim of this R21 Exploratory Grant is to characterize the regulation of CP genes and proteins using a combined genomics and proteomics approach with an emphasis on growth factor signaling. Expression profiles to ADT and the learned helplessness behavioral paradigm will be generated from the choroid plexus and the hippocampus. The hippocampus has been actively investigated as a target brain region for the action of antidepressants and has also been strongly implicated in depression. The inclusion of the hippocampus will provide a tangible framework to evaluate the contribution and/or interaction of the CP with a brain region that is relatively well studied in the context of depression. This study will increase our understanding of choroid plexus biology and its involvement in the action of antidepressants. Knowledge of the mechanisms underlying the actions of antidepressant treatment will increase our understanding of the pathophysiology of depression and could lead to novel therapeutic targets. The results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, further studies would involve studying CSF levels of identified target proteins, their interaction with signaling moieties in various brain regions and studying their ability to impact behavior after manipulating expression and function using molecular and pharmacological tools. ? ?
| Sathyanesan, M; Girgenti, M J; Banasr, M et al. (2012) A molecular characterization of the choroid plexus and stress-induced gene regulation. Transl Psychiatry 2:e139 |
| Girgenti, Matthew J; Collier, Emily; Sathyanesan, Monica et al. (2011) Characterization of electroconvulsive seizure-induced TIMP-1 and MMP-9 in hippocampal vasculature. Int J Neuropsychopharmacol 14:535-44 |
| Girgenti, Matthew J; Hunsberger, Joshua; Duman, Catharine H et al. (2009) Erythropoietin induction by electroconvulsive seizure, gene regulation, and antidepressant-like behavioral effects. Biol Psychiatry 66:267-74 |
