HIPPOCAMPAL FUNCTION ALTERATIONS IN MOUSE MODELS OF LAMB-SHAFFER SYNDROME

Lamb-Shaffer Syndrome (LAMSHF ; OMIM #616803) is a rare genetic disorder caused by mutations in the SOX5 gene, affecting multiple organ systems. Many of the manifestations in LAMSHF patients are of neurological origin, including intellectual disabilities, generalized delays in speech and learning, loss of memory, anxiety, and behaviors associated with Autism Spectrum Disorders (ASD), such as social deficits and stereotypical behavior.
Understanding the pathophysiology of this complex syndrome demands the development of robust animal models to study the individual neural components involved. In this study, we examined hippocampal function using two distinct LAMSHF mouse models: i) a conditional loss-of-Sox5 model during embryonic development specifically in the CA2 region of the hippocampus (Amigo2-cre/Sox5^fl/fl; Sox5^Amigo2), a region crucial for social memory; and ii) a tamoxifen-inducible conditional loss-of-Sox5 model specific to the central nervous system (Sox2-creER^T2/Sox5^fl/fl/YFP+; Sox5^icKO), which enables Sox5 depletion in neural stem cells (NSCs) of the subgranular zone of the dentate gyrus, responsible for adult neurogenesis maintenance, a process crucial for spatial memory.
By combining cellular characterization strategies and transcriptomic tools with an extensive battery of behavioral assays, we found that: i) Sox5^Amigo2 mice exhibited alterations in social memory related to ASD traits, and ii) Sox5^icKO model displayed impaired adult neurogenesis and delay in granule neuron maturation, leading to deficits in spatial and contextual memory, both common features in LAMSHF. These findings provide valuable insights into the neurological mechanisms underlying the syndrome and highlight the potential of these mouse models for the future exploration of therapeutic approaches.