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Updated: Jan 13, 2026

A Fine Motor Task to Study Joint Kinematics in a Preclinical Model of Neurodegenerative Disease
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SEZ6L2 Loss Disrupts Motor Coordination, Cognitive Function, and Synaptic Connectivity.

Julia M Granato1, Nina Silver2, Alison Hobbins2

  • 1Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY.

Biorxiv : the Preprint Server for Biology
|January 8, 2026
PubMed
Summary

The SEZ6L2 gene is crucial for brain function, impacting motor skills, social behavior, and synaptic health. Its absence causes significant neurodevelopmental issues, highlighting SEZ6L2

Keywords:
SEZ6SEZ6LSEZ6L2behaviorcortexmotor coordinationneuron

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • The SEZ6 gene family (SEZ6, SEZ6L, SEZ6L2) is vital for neurodevelopment, synaptic organization, and complement regulation.
  • The specific role of SEZ6L2 in brain function is not well understood.
  • Understanding SEZ6L2's function is key to deciphering neurodevelopmental and neurodegenerative disorders.

Purpose of the Study:

  • To comprehensively characterize the behavioral and neurobiological phenotype of Sez6l2 knockout (KO) mice.
  • To compare the Sez6l2 KO phenotype with Sez6 triple knockout (TKO) mice.
  • To elucidate the non-redundant role of SEZ6L2 in brain function.

Main Methods:

  • Generation and behavioral testing of Sez6l2 KO mice.
  • Comparison of Sez6l2 KO mice with Sez6 TKO mice.
  • Neurobiological analysis including synaptic structure and protein expression.

Main Results:

  • Sez6l2 KO mice exhibit deficits in motor coordination, gait, sociability, sensory processing, and repetitive behaviors.
  • Motor deficits and some behavioral phenotypes worsen with age in Sez6l2 KO mice.
  • Reduced dendritic spine length and decreased postsynaptic protein expression indicate impaired excitatory synaptic connectivity in Sez6l2 KO mice.
  • Sez6 TKO mice show more severe impairments than Sez6l2 KO mice.

Conclusions:

  • SEZ6L2 is a critical and non-redundant regulator of motor, cognitive, and synaptic function.
  • SEZ6L2 dysfunction contributes to neurodevelopmental and neurodegenerative disorders.
  • This study provides mechanistic insights into the SEZ6 family's role in brain health.