Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration (FTLD). However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of FUS, an RNA-binding protein linked to FTLD and amyotrophic lateral sclerosis (ALS), and its potential pathological role in FTLD using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the FTLD-linked behavioral disinhibition. Electro-physiology study and molecular pathway analyses further reveal that FUS differentially regulates synaptic and neuronal properties in the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC), respectively. Moreover, FUS selectively modulates the vHPC-mPFC projection，which is known to mediate the anxiety-like behavior. Our findings unveil the brain region- and synapse-specific role of FUS, whose impairment might lead to the emotional symptoms associated with FTLD.