Developmental origin of serotonin dysfunction in cortical map disruption

Recent developmental transcriptome analysis of human and mouse brain revealed that the great majority of protein-coding genes are expressed differentially across brain regions and over the time, correlating to morphological and functional development of specific brain regions. Moreover, biologically pleiotrophic neurodevelopmental disorder risk genes showed convergence in spatiotemporal gene co-expression networks in the developing brain. It has been proposed that temporal-specific topographic gene expression represents a molecular principle directing neural circuit development, and could underscore a functional intersection of the risk genes for certain phenotypes. However, the precise biological roles of temporally-defined gene function and their long-last impact on the adult nervous system are not well understood. This project aims systematic dissection of temporal- and neuron-specific expression of the serotonin (5-HT) uptake transporter SERT in neural circuit development and the adult CNS in mice. We have identified temporal-specific transient SERT expression along the axons of a unique set of glutamatergic neurons, termed ?5-HT-absorbing neurons?, that do not synthesize 5-HT but uptake 5-HT from extracellular space and prevent excessive trophic 5-HT in specific brain regions during a period of exuberant synaptogenesis that lays down functional circuits. We have selectively knocked out SERT in 5-HT-absorbing neurons in thalamus (SERTTCA?) or in the prefrontal cortex (PFC) and hippocampus (Hip) (SERTCortex?), or in raphe 5-HT-producing neurons (SERTRaphe?) in mice. We have demonstrated that SERT in 5-HT-absorbing axons, not SERT in 5-HT-producing neuron projections, controls cortical map development. We have also demonstrated that SERT in 5-HT-absorbing axons determines neuronal patterning and synaptic architecture of target brain regions. We now hypothesize that the temporal-specific SERT expression in the PFC and Hip pyramidal neurons shapes developmental processes critical for stress responses, while SERT in 5-HT-producing neurons primarily modulates stress neural circuitry in adults. The proposed experiments are to identify long-lasting changes in the adult nervous system arising from disrupted SERT gene function in PFC and Hip 5-HT-absorbing pyramidal neurons. We will test if disruption of SERT in the PFC and Hip 5-HT-absorbing neurons would lead to molecular and synaptic architectural alterations in interconnected brain regions involved in stress responses. We anticipate that studying 5-HT-absorbing neurons in mouse PFC and Hip will reveal a mechanism for SERT to coordinate stress circuit development among distant brain regions, and highlight molecular and cellular origins driving features relevant to mental disorders. By distinguishing SERT function in development and the adult nervous system, our studies will inform when, where and which cell types could potentially contribute to mental disorder treatments.