The serotonin (5HT) system has been widely implicated in the pathophysiology of stress-induced mood disorders, such as anxiety and major depression. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants for treating these disorders. Strongly linked to both mood disorders and the efficacy of SSRI treatment is the regulation of adult hippocampal neurogenesis, a process of generating new neurons from neural precursor cells (NPCs) in the adult dentate gyrus (DG). Importantly, stress, mood disorders, and SSRI treatment have all been shown to alter the 5HT system and influence adult hippocampal neurogenesis, suggesting that 5HT signaling is critical for regulating this process. Currently, we have limited understanding of serotonergic regulation of adult hippocampal neurogenesis, largely due to the broad action of 5HT on the neurogenic niche and lack of information on the expression patterns of 5HT receptors in adult-born cells. Identification of cell-type specific expression of 5HT receptors is challenging because 5HT is capable of binding to 14 distinct 5HT receptor subtypes. To fill these gaps in our understanding, we performed preliminary studies and demonstrated that functional 5HT1A receptors (5HT1ARs) are expressed early in adult NPCs, including type 1 neural stem cells and type 2a early neural progenitors. Strikingly, the functional 5HT1ARs in NPCs are only found in female (but not male) mice. Supporting sex-dependent expression of 5HT1ARs in NPCs, we found that selective deletion of 5HT1ARs in adult NPCs leads to a significant reduction of newborn cells derived from NPCs only in females (not males). These results suggest that expression of 5HT1ARs in NPCs are required for proper lineage progression of NPCs in a sex-dependent manner. These interesting findings sparked several immediate directions we propose to pursue:
In Aim 1, we will examine cell-autonomous and sex-dependent contributions of 5HT1ARs to early neurogenic responses induced by external and serotonergic circuit stimuli;
In Aim 2, we will investigate the causal role of membrane potential in regulating development of normal and 5HT1AR-deficient adult NPCs;
In Aim 3, we will examine the role of 5HT1AR-deleted newborn neurons in hippocampal network activity and hippocampus-dependent behavior.
5HT1ARs are highly implicated in mood disorders and SSRI treatment efficacy. More recently, 5HT1ARs have also been implicated in both cognitive and non-cognitive symptoms of Alzheimer?s disease. Importantly, women are more likely to suffer from these disorders, and have a significantly greater response to SSRIs, as compared to men. The mechanisms underlying sex-dependent vulnerability to these diseases and sensitivity to SSRI treatment are largely unexplored. Results gained from our proposed studies will provide an entry point towards better understanding of the sex differences associated with these diseases and SSRI treatment efficacy. Ultimately, information gained from these studies will enable development of personalized strategies to treat these diseases and improve antidepressant efficacy by targeting adult hippocampal neurogenesis.