title: SorCS2 is required for BDNF-dependent plasticity in the hippocampus.
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 p75NTR, 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 p75NTRwas 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 p75NTRand TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Glerup
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: U
authors.initials: U
authors.lastname: Bolcho
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Mølgaard
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Bøggild
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: C B
authors.initials: CB
authors.lastname: Vaegter
authors.affiliation: Yale School of Medicine, Interdepartmental Neuroscience Program and Medical Scientist Training Program, New Haven, CT, USA.|Department of Psychiatry, VAT CT Healthcare Center, and Yale School of Medicine, New Haven, CT, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Smith
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: J L
authors.initials: JL
authors.lastname: Nieto-Gonzalez
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: P L
authors.initials: PL
authors.lastname: Ovesen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: L F
authors.initials: LF
authors.lastname: Pedersen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: A N
authors.initials: AN
authors.lastname: Fjorback
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Kjolby
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Login
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: M M
authors.initials: MM
authors.lastname: Holm
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: O M
authors.initials: OM
authors.lastname: Andersen
authors.affiliation: MIND Center, Stereology and Electron Microscopy Laboratory, Aarhus University, Aarhus C, Denmark.
authors.forename: J R
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: T E
authors.initials: TE
authors.lastname: Willnow
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Jensen
authors.affiliation: The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience DANDRITE- Nordic EMBL Partnership for Molecular Medicine, Aarhus C, Denmark.|Department of Biomedicine, Aarhus University, Aarhus C, Denmark.|Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nykjaer
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D017475:Receptors, Nerve Growth Factor; C509461:SORCS2 protein, human; C517634:Ngfr protein, mouse; D020813:Receptor, trkB