SEZ6L2 Loss Disrupts Motor Coordination, Cognitive Function, and Synaptic Connectivity

The SEZ6 family, composed of SEZ6, SEZ6L, and SEZ6L2, plays essential roles in neurodevelopment, synaptic organization, and complement regulation. However, the specific contribution of SEZ6L2 to brain function remains largely unexplored. In this study, we provide the first comprehensive behavioral and neurobiological characterization of <i>Sez6l2</i> knockout (KO) mice and directly compare their phenotype with <i>Sez6</i> triple knockout (TKO) mice, which lack all three <i>Sez6</i> family genes. <i>Sez6l2</i> KO mice exhibit impairments across multiple behavioral domains, including motor coordination, gait, sociability, sensory processing, and goal-directed repetitive behaviors. Several phenotypes, particularly motor deficits, worsen with age. Male <i>Sez6l2</i> KO mice also demonstrate enhanced fear learning and increased prepulse inhibition, revealing sex-specific alterations in sensorimotor gating. At the synaptic level, <i>Sez6l2</i> KO mice show reduced dendritic spine length and decreased expression of key postsynaptic proteins suggesting impaired excitatory synaptic connectivity. These structural and molecular abnormalities likely contribute to the observed behavioral deficits. In comparison, <i>Sez6</i> TKO mice display more severe impairments across most measures. Together, these findings establish SEZ6L2 as a critical and non-redundant regulator of motor, cognitive, and synaptic function and provide mechanistic insight into how dysfunction within the SEZ6 family may contribute to neurodevelopmental and neurodegenerative disorders.