The main goal of this project is to understand how changes in the hippocampus may cause pathological aggression. We have previously found that mice with the conditional knockout (KO) of Brain Derived Neurotrophic Factor (BDNF) restricted to the hippocampal area CA3 are more aggressive than their wild type (WT) counterparts. These animals had reduced levels of serotonin (5-HT) and increased expression and activity of the serotonin receptor 3 (5-HTr3), and over-activation of 5-HTr3 increases aggression in wild type mice. The decrease in the levels of 5-HT appeared to cause the up-regulation of 5-HTr3 in BDNF KO mice, because chronic administration of fluoxetine, which elevates concentration of extracellular 5-HT, normalized expression and activity of 5-HTr3, it also reduced aggression. In search for physiological properties of the hippocampus that are regulated by 5-HTr3 and possibly correlate with aggression, we found that 5-HTr3 agonist suppresses induction of hippocampal gamma oscillations by carbachol. During the last fiscal year, we focused on two questions: 1) How loss of BDNF in the hippocampus reduces levels of 5-HT? 2) What mechanisms underlie suppression of gamma oscillations through 5-HTr3? To address the first question, we first examined 5-HT reuptake, which is thought to be influenced by BDNF, and found no difference between KO and control WT mice. This result suggested that lower 5-HT release could be responsible for the reduced 5-HT concentration in KO mice. Accurate measurement of 5-HT release in real time remains a technical challenge, because the release sites are compartmentalized and cannot be readily accessed by a human-made measuring tool. To circumvent this problem, we used fast 5-HT transmission mediated by 5-HTr3 as a measure of 5-HT release. 5-HTr3 is the only ionotrophic 5-HT receptor, which it is a cation channel that opens within milliseconds upon 5-HT release. The current across the channel reflects the amounts of 5-HT released by an electrical stimulus. The channel is expressed in a subpopulation of hippocampal inhibitory neurons (5-HT3 cells), which are readily identifiable in transgenic mice containing GFP gene under the control of 5-HTr3a gene promoter. We began whole cell recordings from hippocampal 5-HT3 cells and preliminary data suggest that 5-HT terminals in BDNF KO mice release less 5-HT than the terminals in WT controls. To address the second question about mechanisms whereby 5-HTr3 activation suppresses gamma oscillations, we examined effects of 5-HTr3 agonist m-CPBG on the cellular properties of 5-HT3 neurons and oscillatory properties of parvalbumine (PV) expressing interneurons, which are the main driving force for gamma oscillations. We found that m-CPBG reduced excitability and firing frequency of 5-HT3 cells by increasing afterhyperpolarization (AHP). This increase in AHP was mediated by calcium-activated small conductance potassium (SK) channels, which were activated as a result of 5-HTr3-mediated depolarization and calcium influx. At the same time, m-CPBG attenuated inhibitory currents in PV-interneurons and increased their firing, which became more random and less coupled to the oscillation phase. Based on these observations, we propose that activation of 5-HTr3 interferes with gamma oscillations by attenuating inhibitory input from 5-HT3 cells to PV interneurons and by increasing random firing of PV cells. Our future goals are to understand how oscillatory activity of hippocampus may relate to aggression and whether 5-HTr3 modulates aggression by changing hippocampal oscillations.
| Warner-Schmidt, Jennifer L; Chen, Emily Y; Zhang, Xiaoqun et al. (2010) A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 68:528-35 |
