In:
Current Neuropharmacology, Bentham Science Publishers Ltd., Vol. 20, No. 12 ( 2022-12), p. 2354-2368
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1570-159X
DOI:
10.2174/1567202619999220209112609
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2022
detail.hit.zdb_id:
2119376-9
Bookmarklink