Sunday, November 24, 2024
11/24/2024
¿ DESCRIPTION (provided by applicant): Dysregulation of serotonin (5-HT) signaling underscores the long-standing theory of circuit perturbations that lead to risks for mental disorders. 5-HT transporter SERT is a critical regulator of 5-HT signaling by limiting 5-HT availability at 5-HT receptors. SERT antagonists (e.g. SSRIs) are the first-line treatments for psychiatric traits. However, polymorphisms that reduce SERT gene expression/functionality are found to be associated with autism, depression, and increased anxiety, and confer structural and functional alterations in brain regions involved in emotion processing. The majority studies of SERT mechanisms focus on brainstem raphe neurons, which produce 5-HT and constitutively express SERT. We recently uncovered previously unknown differences between SERT mechanisms in developing and mature brain. Specifically, we identified a SERT function operating in a distinctly different set of neurons in defined brain regions during a specific time period of cortical maturation. In mice between E17 - P10, SERT is transiently expressed in glutamatergic thalamocortical axons (TCAs) projecting all the sensory cortices and in pyramidal neurons in the PFC and hippocampus. These neurons do not synthesize 5-HT but uptake extracellular 5-HT, termed "5-HT-absorbing neurons". To identify the role of SERT in 5-HT-absorbing neurons, we generated mutant mice with SERT expression disrupted in glutamatergic TCAs (SERTGlu¿), or in pyramidal neurons in the cortex (SERTCortex¿), or in raphe 5-HT-producing neurons (SERTRaphe¿). Studies of SERTGlu¿ and SERTRaphe¿ mice revealed that SERT in 5-HT-absorbing TCAs, not SERT in raphe afferents, is a determinant of columnar patterning and dendritic architecture of the sensory cortex. We hypothesize that SERT expressed in 5-HT-absorbing axons regulates trophic 5-HT signals during circuit establishment, whereas SERT in raphe neuron axons assumes a critical role in regulating synaptic 5-HT in the mature cortex. We propose systematic genetic, anatomical and behavioral experiments investigating how spatiotemporal SERT expression in 5-HT-absorbing axons and SERT in raphe neuron afferents play out to influence cyto- and synapto-architecture in developing and mature cortex and behavior. We anticipate that altered developmental SERT mechanism is likely to define the origins of malfunction of the neural circuits that drive certaub features of te mental disorders, and illuminate the fundamental mechanisms of early life programming of behavior. By uncoupling SERT function in the developing and mature CNS, our studies will inform the cellular sites and timing of SERT expression that underscore the risks for developing mental disorders and that contribute to mental disorder treatments.
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