SorCS2 is required for BDNF-dependent plasticity in the hippocampus
Autor: | 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 |
---|---|
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Neurite Long-Term Potentiation Receptors Cell Surface Receptors Nerve Growth Factor Tropomyosin receptor kinase B Hippocampal formation Hippocampus Receptors N-Methyl-D-Aspartate Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Neurotrophic factors Animals Receptor trkB Molecular Biology Mice Knockout Neurons Neuronal Plasticity biology Brain-Derived Neurotrophic Factor Long-term potentiation Psychiatry and Mental health 030104 developmental biology nervous system Synaptic plasticity biology.protein Psychology Synaptic tagging Neuroscience 030217 neurology & neurosurgery Signal Transduction Neurotrophin |
Zdroj: | 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 |
ISSN: | 1476-5578 1359-4184 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |