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SorCS2 is required for BDNF-dependent plasticity in the hippocampus

Authors :
Andrew H. Smith
Ulrik Bølcho
Christian Bjerggaard Vaegter
Jens R. Nyengaard
Anders Nykjaer
Kimmo Jensen
Thomas E. Willnow
S Bøggild
Simon Glerup
Simon Molgaard
L F Pedersen
Mai Marie Holm
Mads Kjolby
P L Ovesen
Hande Login
Olav M. Andersen
Anja W. Fjorback
Jose Luis Nieto-Gonzalez
Source :
Glerup, S, Bolcho, U, Bøggild, S, Vaegter, C B, Smith, A H, Nieto-Gonzalez, J L, Ovesen, P L, Pedersen, L F, Fjorback, A N, Kjolby, M, Login, H, Holm, M M, Andersen, O M, Nyengaard, J R, Willnow, T E, Jensen, K, Nykjaer, A & Jensen, S M 2016, ' SorCS2 is required for BDNF-dependent plasticity in the hippocampus ', Molecular Psychiatry . https://doi.org/10.1038/mp.2016.108
Publication Year :
2016
Publisher :
Springer Science and Business Media LLC, 2016.

Abstract

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75(NTR), required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75(NTR) was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2(-/-) mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75(NTR) and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.Molecular Psychiatry advance online publication, 26 July 2016; doi:10.1038/mp.2016.108.

Details

ISSN :
14765578 and 13594184
Volume :
21
Database :
OpenAIRE
Journal :
Molecular Psychiatry
Accession number :
edsair.doi.dedup.....0df9bd8c77313960491ff21c27c9835d
Full Text :
https://doi.org/10.1038/mp.2016.108