Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy.

Autor: Jahncke JN; Neuroscience Graduate Program, Oregon Health & Science University, Portland, United States., Miller DS; Neuroscience Graduate Program, Oregon Health & Science University, Portland, United States., Krush M; Neuroscience Graduate Program, Oregon Health & Science University, Portland, United States., Schnell E; Operative Care Division, Portland VA Health Care System, Portland, United States.; Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, United States., Wright KM; Vollum Institute, Oregon Health & Science University, Portland, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2024 Jan 05; Vol. 12. Date of Electronic Publication: 2024 Jan 05.
DOI: 10.7554/eLife.87965
Abstrakt: Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2 , which is required for Dystroglycan glycosylation, show significant impairment of CCK + /CB 1 R + IN development. CCK + /CB 1 R + IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK + /CB 1 R + IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK + /CB 1 R + IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.
Competing Interests: JJ, DM, MK, ES, KW No competing interests declared
Databáze: MEDLINE
Externí odkaz: