title: Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells.
abstract: Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons. Conditional deletion of Dag1, encoding dystroglycan, in pyramidal cells caused loss of CCK-positive basket cell terminals in hippocampus and neocortex. PV-positive basket cell terminals were unaffected in mutant mice, demonstrating interneuron subtype-specific function of dystroglycan. Loss of dystroglycan in pyramidal cells had little influence on clustering of other GABAergic postsynaptic proteins and of glutamatergic synaptic proteins. CCK-positive terminals were not established at P21 in the absence of dystroglycan and were markedly reduced when dystroglycan was ablated in adult mice, suggesting a role for dystroglycan in both formation and maintenance of CCK-positive terminals. The necessity of neuronal dystroglycan for functional innervation by CCK-positive basket cell axon terminals was confirmed by reduced frequency of inhibitory events in pyramidal cells of dystroglycan-deficient mice and further corroborated by the inefficiency of carbachol to increase IPSC frequency in these cells. Finally, neurexin binding seems dispensable for dystroglycan function because knock-in mice expressing binding-deficient T190M dystroglycan displayed normal CCK-positive terminals. Together, we describe a novel function of dystroglycan in interneuron subtype-specific trans-synaptic signaling, revealing correlation of presynaptic and postsynaptic molecular diversity.
  
  
  
  Dystroglycan, an extracellular and transmembrane protein of the dystrophin-glycoprotein complex, is at the center of molecular studies of muscular dystrophies. Although its synaptic distribution in cortical brain regions is long established, function of dystroglycan in the synapse remained obscure. Using mice that selectively lack neuronal dystroglycan, we provide evidence that a subset of GABAergic interneurons requires dystroglycan for formation and maintenance of axonal terminals on pyramidal cells. As such, dystroglycan is the first postsynaptic GABAergic protein for which an interneuron terminal-specific function could be shown. Our findings also offer a new perspective on the mechanisms that lead to intellectual disability in muscular dystrophies without associated brain malformations.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Früh
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Romanos
authors.affiliation: Department of Neuroscience Rita Levi Montalcini, University of Turin, 10124 Turin, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Panzanelli
authors.affiliation: ETH Zurich, 8092 Zurich, Switzerland.
authors.forename: Daniela
authors.identifier: 0000-0001-9709-0150
authors.initials: D
authors.lastname: Bürgisser
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Shiva K
authors.identifier: 0000-0003-0074-1805
authors.initials: SK
authors.lastname: Tyagarajan
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, and.
authors.forename: Kevin P
authors.identifier: 0000-0003-2066-5889
authors.initials: KP
authors.lastname: Campbell
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
authors.forename: Mirko
authors.identifier: 0000-0002-7709-4127
authors.initials: M
authors.lastname: Santello
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland fritschy@pharma.uzh.ch.
authors.forename: Jean-Marc
authors.identifier: 0000-0002-8552-3702
authors.initials: JM
authors.lastname: Fritschy
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism*; D049030:Dystroglycans / Q000235:genetics / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D055879:Gene Knock-In Techniques; D007395:Interneurons / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D018721:Muscarinic Agonists; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D049030:Dystroglycans; D005680:gamma-Aminobutyric Acid; D002217:Carbachol; D002766:Cholecystokinin
keywords: GABA; cholecystokinin; dystroglycanopathy; dystrophin-glycoprotein complex; interneurons; perisomatic