Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

• DOI: 10.7554/elife.87965.2
• Publication Date: 2023-11-22T15:56:13Z
• Authors: Jennifer N. Jahncke; Daniel S. Miller; Milana Krush; Eric Schnell; Kevin M. Wright
• Keywords: 0301 basic medicine; axon guidance; hippocampus; QH301-705.5; seizure; Science; Q; R; 03 medical and health sciences; synapse formation; inhibitory neuron; Medicine; Dystroglycan; Biology (General); Neuroscience

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to actin cytoskeleton. Mutations in Dag1 or genes required for its glycosylation result dystroglycanopathy, type of congenital muscular dystrophy characterized by wide range phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, associated seizure susceptibility multiple mouse models reflect phenotypic dystroglycanopathy neuropathology. Mice model severe due forebrain deletion Pomt2 , which glycosylation, show significant impairment CCK + /CB1R IN development. axons failed properly target somatodendritic compartment pyramidal neurons hippocampus, resulting defects increased susceptibility. lacking intracellular domain have milder axon targeting, but exhibit dramatic changes inhibitory indicating critical postsynaptic role this domain. In contrast, function was normal mice mild partially reduced glycosylation. Collectively, these data elevated are hallmarks plays an important organizing functional synapse assembly.