Altered Expression and In Vivo Activity of mGlu5 Variant a Receptors in the Striatum of BTBR Mice: Novel Insights Into the Pathophysiology of Adult Idiopathic Forms of Autism Spectrum Disorders.

Autor:	Matrisciano F; The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA., Locci V; The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA., Dong E; The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.; Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA., Nicoletti F; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.; IRCCS Neuromed, Pozzilli, Italy., Guidotti A; The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.; Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA., Grayson DR; The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA.; Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA.
Jazyk:	angličtina
Zdroj:	Current neuropharmacology [Curr Neuropharmacol] 2022 Nov 15; Vol. 20 (12), pp. 2354-2368.
DOI:	10.2174/1567202619999220209112609
Abstrakt:	Background: mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Objective: Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. Methods: Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. Results: Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. Conclusion: These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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