Serotonin plays an important role in the pathophysiology and pharmacotherapeutic treatment of mood and anxiety disorders. Consequently there is an urgent need to understand the mechanisms that control serotonergic function in the brain. An important aspect of this task is understanding the factors that control the activity of serotonin secreting neurons. Previous studies have identified serotonin receptors of the 5-HT1A subtype as important regulators of the activity of serotonergic neurons. Specifically, these so called "serotonin autoreceptors" have been hypothesized to mediate autoinhibition in serotonergic nuclei and their downregulation has been hypothesized to mediate some of the effects of chronic antidepressant treatment on serotonergic function. Yet, surprisingly and in spite of considerable effort, we still know very little about the specific mechanisms supporting 5-HT1A autoreceptor mediated autoinhibition and how this process participates in the regulation of serotonergic cell activity. This important gap in our understanding reflects technical limitations in our ability to selectively control the activity of serotonergic neurons that have made it difficult to directly study autoreceptor mechanisms. In the current application we propose to use recent technical developments including optogenetics in genetically modified model mice to approach this problem. In preliminary results we show that this approach allows for the unambiguous recording of 5-HT1A receptor-mediated autoinhibitory currents in the Dorsal Raphe Nucleus, the principal serotonergic cell group innervating the forebrain. We propose to extend these findings in three directions, 1) to elucidate, at the level o their synaptic organization, how serotonergic neurons control their own activity through 5-HT1A autoreceptors, 2) to determine the conditions under which 5-HT1A autoreceptor-mediated autoinhibition becomes functional and 3) to investigate how chronic antidepressants modify 5-HT1A receptor-mediated autoinhibition and other cellular processes to modulate the activity of serotonergic neurons. By addressing these issues we hope to help develop a better understanding of the function and regulation of 5-HT1A autoreceptors in the brain and thus contribute to the development of more effective pharmacotherapeutic approaches for the treatment of mood and anxiety disorders.

Public Health Relevance

Many antidepressants act by regulating the actions of the neurotransmitter serotonin in the brain. In this application we propose to use novel state of the art approaches to study how serotonin secreting neurons regulate their own activity through serotonin autoreceptors and the regulation of this process by antidepressants. Understanding these processes can be expected to contribute to the development of better pharmacotherapeutic approaches for the treatment of mood and anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH100850-01A1
Application #
8597662
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (04))
Program Officer
Nadler, Laurie S
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$224,464
Indirect Cost
$74,464
Name
Wayne State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Feliciano, Pedro; Andrade, Rodrigo; Bykhovskaia, Maria (2013) Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the hippocampus. J Neurosci 33:18319-30