Endogenous 5-HT1A receptor-mediated feedback inhibition of dorsal raphe serotonin neurons in the SERT-knockout mouse

MARIANO SOIZA REILLY; KATHERINE E PRICE; KATHRYN G. COMMONS

New Orleans

Congreso; 42nd Society for Neuroscience Annual Meeting; 2012

Society for Neuroscience

<!-- /* Font Definitions */ @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Arial; panose-1:2 11 6 4 2 2 2 2 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} @font-face {font-family:Cambria; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-fareast-font-family:Cambria; mso-bidi-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-fareast-font-family:Cambria; mso-hansi-font-family:Cambria;} @page WordSection1 {size:8.5in 11.0in; margin:1.0in 1.25in 1.0in 1.25in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.WordSection1 {page:WordSection1;} --> Dysregulation of forebrain serotonin (5-HT) released from 5-HT neurons located in the dorsal raphe nucleus (DR) has been implicated in mood disorders including depression and anxiety.  Moreover, these alterations were associated with adaptive changes in 5-HT1A receptor-mediated feedback inhibition in the DR.  The 5-HT transporter knockout mice (SERT-/-) have been used as a model of mood disorders.  In this model, alterations on 5-HT neurotransmission have been described. However whether activity within DR 5-HT networks could be topographically altered in response to an acute stress, and how 5-HT1A receptor-mediated feedback pathways coordinately adapt in these mice remain poorly understood.  We examined in wild type (WT) and SERT-/- mice the swim-induced activation of DR 5-HT neurons at different rostro-caudal levels.  For this, we used immunohistochemistry to evaluate Fos expression within DR 5-HT cells, identified by the presence of the enzyme tryptophan hydroxylase.  To evaluate 5-HT1A receptor-dependent feedback, we measured Fos expression in DR-5-HT cells in mice that were pre-treated systemically with the selective 5-HT1A antagonist WAY-100635.  In this way, increases in Fos expression after 5-HT1A receptor blockade would implicate previous endogenous inhibition through 5-HT1A-mediated mechanisms.  In the absence of WAY-100635, analysis of Fos-containing 5-HT cells in WT and SERT-/- animals showed similar levels of Fos-activation in response to the swim stress in most of the DR regions.  Administration of WAY-100635 in WT and SERT-/- mice preceding the swim potentiated Fos activation in 5-HT cells in a region-specific manner within the DR.  Moreover, SERT-/- mice showed a more pronounced effect of WAY-100635 than WT mice, indicating adaptive changes of 5-HT1A receptor-mediated feedback inhibition in the SERT-/- mice.  Although DR 5-HT1A receptors are known to be desensitized in this model, these results provide evidence that 5-HT networks remain strongly influenced by feedback inhibition, suggesting that adaptations within long-feedback loops may underlie this effect.  Further understanding of these adaptive mechanisms will contribute to understanding the dysfunction of 5-HT neurons in this model of mood disorders.