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Dystroglycan Mediates Homeostatic Synaptic Plasticity at Gabaergic Synapses

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Dystroglycan Mediates Homeostatic Synaptic Plasticity at Gabaergic Synapses Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses Horia Pribiag1, Huashan Peng1, Waris Ali Shah, David Stellwagen2, and Salvatore Carbonetto2 Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Research Institute of McGill University Health Center, Montréal, QC, Canada H3G 1A4 Edited by Joshua R. Sanes, Harvard University, Cambridge, MA, and approved March 27, 2014 (received for review November 24, 2013) Dystroglycan (DG), a cell adhesion molecule well known to be dispensable for GABAergic synapse formation in hippocampal essential for skeletal muscle integrity and formation of neuromus- cultures (17), although adult mice lacking full-length dystrophin cular synapses, is also present at inhibitory synapses in the central show reduced clustering of GABAARs in the hippocampus and nervous system. Mutations that affect DG function not only result other brain regions (16, 19, 20). Because dystrophin localization at in muscular dystrophies, but also in severe cognitive deficits and GABAergic synapses depends on DG (17), these findings suggest epilepsy.HerewedemonstratearoleofDGduringactivity- that DG may regulate the plasticity of mature GABAergic syn- dependent homeostatic regulation of hippocampal inhibitory apses. Homeostatic synaptic plasticity is widely thought to be es- synapses. Prolonged elevation of neuronal activity up-regulates sential for brain function and involves the reciprocal regulation DG expression and glycosylation, and its localization to in- hibitory synapses. Inhibition of protein synthesis prevents the of glutamatergic and GABAergic synapses to stabilize neuronal activity (21). Chronic elevation of neuronal activity is associated activity-dependent increase in synaptic DG and GABAA receptors with an increase in synaptic GABA Rs (22, 23), but the mecha- (GABAARs), as well as the homeostatic scaling up of GABAergic A synaptic transmission. RNAi-mediated knockdown of DG blocks nistic details are incompletely understood. homeostatic scaling up of inhibitory synaptic strength, as does Here, we assess the roles of DG and α-DG glycosylation in knockdown of like-acetylglucosaminyltransferase (LARGE)—a regulating the expression of homeostatic synaptic plasticity at glycosyltransferase critical for DG function. In contrast, DG is not GABAergic synapses. We find that in mature hippocampal cul- required for the bicuculline-induced scaling down of excitatory tures, prolonged elevation of neuronal activity up-regulates DG synaptic strength or the tetrodotoxin-induced scaling down of in- expression and the coclustering of α-DG and GABAARs. In- hibitory synaptic strength. The DG ligand agrin increases GABAergic hibition of protein synthesis or knockdown of DG blocks ho- synaptic strength in a DG-dependent manner that mimics homeo- meostatic scaling up of GABAergic synaptic strength. Knockdown static scaling up induced by increased activity, indicating that activa- of the selective α-DG glycosyltransferase LARGE also blocks tion of this pathway alone is sufficient to regulate GABAAR homeostatic scaling up, suggesting a role for ligand binding. Fur- trafficking. These data demonstrate that DG is regulated in a phys- thermore, exogenous application of agrin—a ligand for glycosy- iologically relevant manner in neurons and that DG and its glycosyl- lated α-DG—is sufficient to scale up GABAergic synaptic strength ation are essential for homeostatic plasticity at inhibitory synapses. in a DG-dependent fashion. These data identify a mechanism α muscular dystrophy | excitation–inhibition balance | dystrophin | whereby expression of glycosylated -DG is linked to neuronal AMPA receptors | retardation activity level and is essential for homeostatic scaling up of GABAergic synaptic strength by regulating GABAAR abundance uscular dystrophies are often associated with mild to se- at the synapse. Mvere cognitive deficits, epilepsy, and other neurological deficits (1–3). This is particularly evident in muscular dystrophies Significance caused by mutations that affect glycosylation of the membrane glycoprotein α-dystroglycan (α-DG) (4). α-DG docks with trans- Normal levels of brain activity result from a fine balance of membrane β-DG to form the functional core of the dystrophin- excitation and inhibition, and disruption of this balance may associated glycoprotein complex (DGC) that links adhesive pro- underlie many neurological disorders. Physiologically, homeo- teins in the extracellular matrix to dystrophin (5). α-DG is heavily static synaptic plasticity maintains this balance, though the glycosylated and interacts via its carbohydrate side chains with molecular underpinnings of this plasticity, necessary to explain laminin and laminin G-like domains in a variety of proteins in- brain dysfunction and define therapies, are not well under- cluding agrin, perlecan, slit, neurexin, and pikachurin (6–10). Key stood. Here we have described regulation of inhibitory syn- carbohydrate residues are added onto α-DG by several glyco- aptic plasticity by dystroglycan, a cell adhesion molecule that syltransferases, most notably like-acetylglucosaminyltransferase forms a scaffold at inhibitory (GABAergic) synapses and home- (LARGE) (11). LARGE is necessary for functional glycosylation of ostatically regulates the abundance of GABAA receptors in the α-DG (12), and is mutated in muscular dystrophies associated with postsynaptic density. These data may explain the epilepsy and severe cognitive deficits (4). cognitive deficits observed in individuals lacking functional DG was first identified in the nervous system (13), where it is dystroglycan. important during development for neuroblast migration (14), Author contributions: H. Pribiag, D.S., and S.C. designed research; H. Pribiag, H. Peng, and axon guidance (7), and ribbon synapse formation (8). At neu- W.A.S. performed research; H. Pribiag, H. Peng, W.A.S., and D.S. analyzed data; and romuscular synapses, DG is required for the stabilization of H. Pribiag, D.S., and S.C. wrote the paper. acetylcholine receptors in the postsynaptic density and contrib- The authors declare no conflict of interest. utes to the accumulation of acetylcholinesterase (10, 15). How- This article is a PNAS Direct Submission. ever, the function of DG at central synapses remains essentially 1H. Pribiag and H. Peng contributed equally to this work. unknown. In the mature central nervous system (CNS), neuronal 2To whom correspondence may be addressed. E-mail: [email protected] or sal. DGC components are exclusively colocalized with GABAA [email protected]. – receptors (GABAARs) in multiple brain regions (16 18), raising This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. the possibility for a role in GABAAR regulation. However, DG is 1073/pnas.1321774111/-/DCSupplemental. 6810–6815 | PNAS | May 6, 2014 | vol. 111 | no. 18 www.pnas.org/cgi/doi/10.1073/pnas.1321774111 Downloaded by guest on September 26, 2021 Results surface A α-DG GABA(A)R β3 α-DG/β3/MAP2 C GABA(A)R γ2 Characterization of the DG Complex at Hippocampal GABAergic Synapses. We used immunohistochemical staining with mAb IIH6 antibody, which recognizes functionally glycosylated α-DG (24), and antibodies to GABAAR α1, to reveal that virtually all Control Control GABAAR α1 clusters colocalize with α-DG clusters in the CA3 stratum pyramidale of WT mice (Fig. S1 B and C). However, in Mdx mice—which do not express the full-length isoform of dystrophin (5) that anchors DG at the cell surface (25)—we α 24 hrs) observed substantially reduced expression of -DG and fewer 24 hrs) GABAAR α1clustersintheCA3region(Fig. S1D). Similarly, Myd mice, which have hypoglycosylated α-DG due to a muta- tion in the glycosyltransferase LARGE (26), also displayed Bicuculline ( reduced α-DG and α1 clusters in CA3 hippocampus (Fig. S1E). Bicuculline ( We further examined the localization of DG using mature hippocampal cultures and found that α-DG colocalizes with β-DG Surface α-DG GABA(A)R β3 and with GABAAR clusters apposed to GAD65 puncta, but that B D GABA(A)R γ2 α-DG does not colocalize with AMPA receptor (AMPAR) clus- 250 *** 200 *** 200 ** ters (Fig. S2A). We also observed a high degree of colocalization 200 between α-DG and several proteins previously identified as part 150 150 150 of the DGC at neuromuscular synapses, including agrin, ezrin, 100 100 nNOS, and utrophin (15, 27) (Fig. S2B). Furthermore, using im- 100 50 munoprecipitation from brain lysates, we found that α-DG forms 50 50 a supramolecular complex, not only with β-DG, but also with Area (%Ctrl) Cluster Total 0 Area (%Ctrl) Cluster Total 0 Area (%Ctrl) Cluster Total 0 Ctrl Bic Ctrl Bic Ctrl Bic GABAAR subunits α1andβ2/3, as well as with the inhibitory C Surface Ctrl Total synapse scaffolding protein gephyrin (Fig. S2 ). Taken together, E Ctrl Bic F these findings suggest that the neuronal DGC is part of the * Bic ** α-DG postsynaptic scaffold at mature inhibitory synapses and may sta- Surface 150 ** * 150 * bilize and/or regulate the abundance of GABAARs. n.s. β-DG 100 100 Activity-Dependent Homeostatic Regulation of α-DG and GABAARs. GABA(A)R At neuromuscular synapses, DG is required for the stabiliza- β3 %Control %Control tion of acetylcholine receptors in the postsynaptic density (15). α-DG 50 50 Total In hippocampal neurons, however, previous work has reported β-DG that DG is not necessary for GABAergic synapse formation and GABA(A)R β3 0 0 is recruited after the appearance of GABAAR clusters (17), β-tubulin GABA(A)R GABA(A)R
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