SorCS2 is required for BDNF-dependent plasticity in the hippocampus

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• SorCS2 (Sortilin related receptor 1) is a Vps10p-domain receptor family member involved in neuronal health.
• Genetic studies link SORCS2 to increased risk for bipolar disorder, schizophrenia, and ADHD.
• SorCS2's precise role in synaptic function and its connection to neurological disorders remain unclear.

Purpose of the Study:

• To investigate the function of SorCS2 in hippocampal synaptic plasticity and its interaction with neurotrophin receptors.
• To elucidate the molecular mechanisms by which SorCS2 influences neuronal signaling and behavior.
• To establish the link between SorCS2, BDNF signaling, and mental health disorders.

Main Methods:

• Utilized SorCS2-deficient (Sorcs2-/-) mice to study synaptic plasticity.
• Investigated interactions between SorCS2, p75^NTR, and TrkB using co-immunoprecipitation and biochemical assays.
• Assessed BDNF-induced signaling, neurite outgrowth, spine formation, and behavioral phenotypes in Sorcs2-/- mice.

Main Results:

• SorCS2 deficiency eliminated N-methyl-d-aspartate receptor-dependent synaptic plasticity in hippocampal neurons.
• SorCS2 forms complexes with p75^NTR and binds TrkB in an activity-dependent manner, facilitating TrkB translocation for synaptic potentiation.
• SorCS2-deficient neurons showed impaired BDNF-induced TrkB autophosphorylation, downstream signaling, neurite outgrowth, and spine formation.
• Sorcs2-/- mice exhibited deficits in long-term memory, increased risk-taking behavior, heightened stress susceptibility, and impaired prepulse inhibition.

Conclusions:

• SorCS2 acts as an essential coreceptor for both p75^NTR and TrkB in hippocampal neurons.
• SorCS2 is critical for activity-dependent TrkB receptor trafficking and downstream signaling, underpinning synaptic plasticity and memory formation.
• SorCS2 represents a potential molecular link between pro-BDNF/BDNF signaling pathways and the pathophysiology of major mental disorders.