Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells
| Autor: | Simon Früh, Mirko Santello, Jennifer Romanos, Shiva K. Tyagarajan, Patrizia Panzanelli, Daniela Bürgisser, Kevin P. Campbell, Jean-Marc Fritschy |
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| Přispěvatelé: | University of Zurich, Fritschy, Jean-Marc |
| Rok vydání: | 2016 |
| Předmět: |
Male
musculoskeletal diseases 0301 basic medicine congenital hereditary and neonatal diseases and abnormalities animal structures Interneuron Presynaptic Terminals Neurexin 10050 Institute of Pharmacology and Toxicology 610 Medicine & health Muscarinic Agonists Biology Inhibitory postsynaptic potential Mice 03 medical and health sciences 0302 clinical medicine Interneurons Parasympathetic Nervous System Basket cell Postsynaptic potential medicine Dystroglycan Animals Gene Knock-In Techniques Dystroglycans Neural Cell Adhesion Molecules gamma-Aminobutyric Acid Mice Knockout Pyramidal Cells General Neuroscience Calcium-Binding Proteins fungi Excitatory Postsynaptic Potentials 2800 General Neuroscience Articles musculoskeletal system Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure nervous system biology.protein 570 Life sciences biology Carbachol Female Pikachurin Pyramidal cell Cholecystokinin Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 ofDag1, 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.SIGNIFICANCE STATEMENTDystroglycan, 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. |
| Databáze: | OpenAIRE |
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