TAAR1 deficiency impairs mitochondrial dynamics and synaptic integrity in the medial prefrontal cortex and associated cognition in mice

Accumulating evidence suggests that the trace amine-associated receptor 1 (TAAR1) in the medial prefrontal cortex (mPFC) is involved in modulating some areas of behavior related to psychiatric disorders and neurochemical transmission, but the molecular mechanism is unclear. In this study, we used the mPFC transcriptome of TAAR1 knockout mice to investigate the molecular cues associated with TAAR1 and to further explore the potential mechanisms. Following RNA-seq data analysis, several significant protein alterations related to mitochondrial and synaptic function, as well as changes in mitochondrial structure and function, were further verified by a series of experiments including RT-qPCR, Western blot, transmission electron microscopy, and flow cytometry. Mitochondrial dysfunction in the mPFC manifested by decreased mitochondrial membrane potential, increased mitochondrial perimeter, and disturbed fission-fusion dynamics was observed in mice lacking TAAR1. Additionally, synaptic alterations, such as reduced postsynaptic density thickness and decreased expression of postsynaptic-related proteins (p-NR2B, PSD95, and CaMKIIα), suggested impaired synaptic signaling. Behaviorally, TAAR1 knockout mice displayed cognitive deficits, particularly in learning and spatial memory, without significant changes in anxiety- or depressive-like behaviors. Together, these findings suggest that TAAR1 plays a critical role in maintaining mitochondrial and synaptic integrity in the mPFC, and its deficiency may contribute to cognitive impairment, providing novel insights into the mechanisms underlying neuropsychiatric disorders.