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

Wang et al. report that FUS regulates synaptic transmission and neuronal-firing properties in a brain region-specific manner, and provide evidence that the synaptic dysfunction of the vHPC-mPFC circuit caused by loss of FUS underlies 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. 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 fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (Fus(cKO)). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Automated summary

Wang et al. demonstrate that FUS plays a role in regulating synaptic transmission and neuronal properties in a brain region-specific manner, and suggest that the dysfunction of the vHPC-mPFC circuit caused by loss of FUS contributes to FTLD-linked behavioural disinhibition. This study sheds light on the synaptic function of FUS and its potential pathological role in frontotemporal lobar degeneration, providing insights into the development of neurological disorders.