Analysis of social interactions in a genetic model of Lamb-Shaffer syndrome autism spectrum disorders.

Abstract

Many neurodevelopmental disorders associated with deficiencies in social interaction, language difficulties and repetitive behaviours are grouped under the name of autism spectrum disorders (ASD). Although the genetic causes of ASD are complex, one of the genes that have been associated with ASD is Sox5. In humans, heterozygous genetic alterations comprising Sox5 cause Lamb-Shaffer syndrome (OMIM #616803). Sox5 encodes a transcription factor with important functions in the control of neurogenesis (Li et al., 2022) and in the specification of projection neurons of the cerebral cortex (Lai et al., 2008). Moreover, it has been described that the CA2 region of the hippocampus is fundamental in social behaviour in mice, a region where we have previously shown that Sox5 is expressed (Fernandez-Lamo et al., 2019; Hitti & Siegelbaum, 2014). Using conditional Sox5 mutant mice specific for the CA2 region (Amigo2-cre/Sox5fl/fl;Sox5Amigo2) we have determined that robust lack of Sox5 expression causes PCP4 level decrease in more than half of the pyramidal neurons in CA2. Furthermore, using an extensive battery of behavioural assays we have determined that Sox5Amigo2 mutant mice: i) exhibit normal basic reflexes, weight, locomotion abilities, and anxiety levels; ii) exhibit a good performance in Morris water maze test; iii) present normal social preference and iv) both males and female lose social recognition memory. Preliminary data also suggest possible alterations in the expression of neuronal activity marker cFos in the CA2 region of Sox5Amigo2 mice after performing social interaction tasks. Thus, we propose that Sox5Amigo2 mice could provide a new model of ASD, based on cellular and functional alterations of the CA2 region of the hippocampus, that serves to understand the hippocampal component in the pathophysiology of ASD in Lamb-Shaffer syndrome and for the testing of new therapeutic strategies.