Dystroglycan Mediates Homeostatic Synaptic Plasticity at GABAergic Synapses

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Apr 23

PMID 24753587

Citations 47

Authors

Horia Pribiag

Huashan Peng

Waris Ali Shah

David Stellwagen

Salvatore Carbonetto

Affiliations

Soon will be listed here.

Abstract

Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.

Citing Articles

Release your inhibitions: The cell biology of GABAergic postsynaptic plasticity.

Welle T, Smith K Curr Opin Neurobiol. 2024; 90:102952.

PMID: 39721557 PMC: 11839402. DOI: 10.1016/j.conb.2024.102952.

The Role of Brain Plasticity in Neuromuscular Disorders: Current Knowledge and Future Prospects.

Alonge P, Gadaleta G, Urbano G, Lupica A, Di Stefano V, Brighina F Brain Sci. 2024; 14(10).

PMID: 39451985 PMC: 11506792. DOI: 10.3390/brainsci14100971.

GABAergic synaptic scaling is triggered by changes in spiking activity rather than AMPA receptor activation.

Gonzalez-Islas C, Sabra Z, Fong M, Yilmam P, Yong N, Engisch K Elife. 2024; 12.

PMID: 38941139 PMC: 11213567. DOI: 10.7554/eLife.87753.

Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition.

Nuwer J, Povysheva N, Jacob T Neuropharmacology. 2023; 237:109587.

PMID: 37270156 PMC: 10527172. DOI: 10.1016/j.neuropharm.2023.109587.

A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop.

Trotter J, Wang C, Zhou P, Nakahara G, Sudhof T Nat Commun. 2023; 14(1):1771.

PMID: 36997523 PMC: 10063607. DOI: 10.1038/s41467-023-36872-8.

References

Sumita K, Sato Y, Iida J, Kawata A, Hamano M, Hirabayashi S . Synaptic scaffolding molecule (S-SCAM) membrane-associated guanylate kinase with inverted organization (MAGI)-2 is associated with cell adhesion molecules at inhibitory synapses in rat hippocampal neurons. J Neurochem. 2006; 100(1):154-66. DOI: 10.1111/j.1471-4159.2006.04170.x. View

Moore C, Hewitt J . Dystroglycan glycosylation and muscular dystrophy. Glycoconj J. 2008; 26(3):349-57. DOI: 10.1007/s10719-008-9182-0. View

Sugita S, Saito F, Tang J, Satz J, Campbell K, Sudhof T . A stoichiometric complex of neurexins and dystroglycan in brain. J Cell Biol. 2001; 154(2):435-45. PMC: 2150755. DOI: 10.1083/jcb.200105003. View

Montanaro F, Gee S, Jacobson C, Lindenbaum M, Froehner S, Carbonetto S . Laminin and alpha-dystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway. J Neurosci. 1998; 18(4):1250-60. PMC: 6792747. View

Sekiguchi M, Zushida K, Yoshida M, Maekawa M, Kamichi S, Yoshida M . A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice. Brain. 2008; 132(Pt 1):124-35. DOI: 10.1093/brain/awn253. View

Sato S, Omori Y, Katoh K, Kondo M, Kanagawa M, Miyata K . Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation. Nat Neurosci. 2008; 11(8):923-31. DOI: 10.1038/nn.2160. View

Costa-Mattioli M, Sossin W, Klann E, Sonenberg N . Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009; 61(1):10-26. PMC: 5154738. DOI: 10.1016/j.neuron.2008.10.055. View

Levi S, Grady R, Henry M, Campbell K, Sanes J, Craig A . Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation. J Neurosci. 2002; 22(11):4274-85. PMC: 6758826. DOI: 20026440. View

Adams M, Anderson K, Froehner S . The alpha-syntrophin PH and PDZ domains scaffold acetylcholine receptors, utrophin, and neuronal nitric oxide synthase at the neuromuscular junction. J Neurosci. 2010; 30(33):11004-10. PMC: 2936458. DOI: 10.1523/JNEUROSCI.1930-10.2010. View

10.

Hendriksen J, Vles J . Neuropsychiatric disorders in males with duchenne muscular dystrophy: frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive--compulsive disorder. J Child Neurol. 2008; 23(5):477-81. DOI: 10.1177/0883073807309775. View

11.

Godfrey C, Foley A, Clement E, Muntoni F . Dystroglycanopathies: coming into focus. Curr Opin Genet Dev. 2011; 21(3):278-85. DOI: 10.1016/j.gde.2011.02.001. View

12.

Mehler M . Brain dystrophin, neurogenetics and mental retardation. Brain Res Brain Res Rev. 2000; 32(1):277-307. DOI: 10.1016/s0165-0173(99)00090-9. View

13.

Ibraghimov-Beskrovnaya O, Ervasti J, Leveille C, Slaughter C, Sernett S, Campbell K . Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature. 1992; 355(6362):696-702. DOI: 10.1038/355696a0. View

14.

Gingras J, Rassadi S, Cooper E, Ferns M . Synaptic transmission is impaired at neuronal autonomic synapses in agrin-null mice. Dev Neurobiol. 2007; 67(5):521-34. DOI: 10.1002/dneu.20304. View

15.

Peng Y, Zeng S, Song H, Li M, Yamada M, Yu X . Postsynaptic spiking homeostatically induces cell-autonomous regulation of inhibitory inputs via retrograde signaling. J Neurosci. 2010; 30(48):16220-31. PMC: 6634825. DOI: 10.1523/JNEUROSCI.3085-10.2010. View

16.

De Sarro G, Ferreri Ibbadu G, Marra R, Rotiroti D, Loiacono A, Di Paola E . Seizure susceptibility to various convulsant stimuli in dystrophin-deficient mdx mice. Neurosci Res. 2004; 50(1):37-44. DOI: 10.1016/j.neures.2004.05.007. View

17.

Peng H, Xie H, Rossi S, Rotundo R . Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J Cell Biol. 1999; 145(4):911-21. PMC: 2133180. DOI: 10.1083/jcb.145.4.911. View

18.

Dallerac G, Perronnet C, Chagneau C, Leblanc-Veyrac P, Samson-Desvignes N, Peltekian E . Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse. Neurobiol Dis. 2011; 43(3):635-41. DOI: 10.1016/j.nbd.2011.05.012. View

19.

Turrigiano G . Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol. 2011; 4(1):a005736. PMC: 3249629. DOI: 10.1101/cshperspect.a005736. View

20.

Daniels M . The role of agrin in synaptic development, plasticity and signaling in the central nervous system. Neurochem Int. 2012; 61(6):848-53. PMC: 3413752. DOI: 10.1016/j.neuint.2012.02.028. View