Impact of Lis1 mutation on the development of somatostatin-positive interneurons in the cingulate cortex

Approximately 25% of all cortical neurons are inhibitory interneurons, with somatostatin-positive interneurons (SST+ interneurons) representing a distinct subtype expressing both somatostatin and GABA. These cells form synapses with pyramidal neurons and other interneurons, crucial for modulating cortical information processing and maintaining excitation/inhibition balance. Originating from the medial ganglionic eminence, SST+ interneurons follow a tangential pathway to the cortex, making them susceptible to gene mutations affecting neuronal migration. One such gene, Platelet-activating factor acetylhydrolase 1B subunit alpha (Pafah1b1 or Lis1), regulates various cellular processes. Lis1 mutations are associated with lissencephaly in humans and disrupt neural migration, leading to cortical and hippocampal disorganization, spatial learning deficits, epilepsy, and imbalances in excitation/inhibition. To study the role of Lis1 in SST+ interneurons, we created a novel animal model with Lis1 gene deleted specifically in SST+ interneurons (SST-Lis1 animals). Our results show a decreased number of SST+ neurons in the anterior cingulate and the retrosplenial cortex of SST-Lis1 animals; this decreased number was significant either in the total number of cortical SST+ neurons or in the number within individual layers (layers 2/3 to 6). We also analyzed the tangential migration of SST+ neurons during embryonic development (E14.5 and E16.5). We detected a reduced number of migrating SST+ interneurons in the developing cortex, suggesting the involvement of Lis1. in SST+ interneuron development. Further research is needed to understand the mechanisms underlying this reduction and its functional implications.