SorCS2 Regulates Dopaminergic Wiring and Is Processed into an Apoptotic Two-Chain Receptor in Peripheral Glia

Abstract

Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

“…Loss of SorCS1 also affects trafficking of the synaptic organizing proteins Nlgns and Nrxns, which regulate many aspects of synapse development and function (Krueger et al, 2012), and have been linked to autism (Baudouin et al, 2012; Morrow et al, 2008; Tabuchi et al, 2007) and schizophrenia (Etherton et al, 2009; Rujescu et al, 2009). In addition to SorCS1's synaptic function, SorCS2 has recently been shown to act as a coreceptor of the p75 neurotrophin receptor in mediating proneurotrophin-induced growth cone collapse (Anastasia et al, 2013; Deinhardt et al, 2011; Glerup et al, 2014). These findings suggest that other SorCS family members could affect neuronal morphology and wiring in different ways.…”

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

“…Specifically, a complementary mechanism is now emerging where the BDNF 66Met prodomain may act as a ligand to receptor targets such as SorCS2, 21 a member of the VPS10 domain containing receptor family, 22 which is a recently established proneurotrophin receptor involved in dopaminergic wiring. 23 An effect of the Val66Met polymorphism at the cellular level is also evident, with neuronal morphology and physiology being altered both within the hippocampus and the medial-prefrontal cortex of 66Met allele-carrying genetically modified mice. Within the hippocampus, the 66Met allele is associated with reductions in BDNF protein expression and neurogenesis, 24 as well as decreased hippocampal volume, dendritic complexity and fractal dimensionality.…”

BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity

“…A mechanism for this effect, given a lack of defined circuitry, remains difficult to assess. However, a biochemical clue is a recent report which shows that the 66Met-containing BDNF prodomain binds with altered affinity to the SorCS2 receptor 51 -which plays an important role in dopaminergic wiring 52 -to elicit biological effects. 53 Given this role of SorCS2 on the development of dopaminergic innervation 51,52 in the brain, and the established role of dopamine in schizophrenia 54 and on PPI, [55][56][57] it is possible that hBDNF Val/Met mice show altered catecholamine innervation of the PPI circuitry, rendering the PPI performance of this genotype group more vulnerable to environmental factors such as stress.…”