PIANP/LEDA-1 INFLUENCES CEREBELLAR GREY MATTER HISTOARCHITECTURE, APOPTOSIS AND REGIONAL STRESS MARKER EXPRESSION

The primarily neuronally localised protein PIANP/LEDA-1 binds to the N-terminal domain of GABA-B receptors as well as the inhibitory immunoglobuline-like type 2 receptor PILRa [1]. Loss of function mutations are associated with global development delay and signs of intellectual disability in humans whilst knockout mice present with features of autism spectrum disorder (ASD)-like behaviour as well as heightened anxiety[2]. As we previously showed, PIANP knockout mice display altered gross brain morphology and marked alterations of hippocampal adult neurogenesis [2, 3].
To shed further light on the specific cellular processes underlying the ASD-like phenotype, we compared male homozygous PIANP knockout mice (PIANPko) to both wildtype C57BL6/N mice and mice floxed at the PIANP locus (PIANPflp).
Knockouts showed cerebellar alterations on both a structural as well as a cellular level. Furthermore, PIANPko animals displayed markedly increased cerebellar apoptosis and region-specific alterations of stress markers linked to the endoplasmic reticulum, mTOR activation and oxidative stress. We observed specific alterations for different cerebellar areas and cortical layers, suggesting a complex structural and cellular interaction. Taken together, these results shed further light on region-specific processes which seem to be involved in the observed ASD-like phenotype of knockout mice. Further research is necessary to characterise the precise interaction of these processes in effecting these behaviours in both humans and mice.
Bibliography
1. Kogure A et al. 2011
2. Winkler M et al. 2020
3. Winkler M et al. 2020