SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

Background Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression. Methods We derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons. Results We show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. Conclusions We formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments. ### Competing Interest Statement The authors have declared no competing interest.