Title: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
Volume: 20
Issue: 12
Author(s): Francesco Matrisciano*, Valentina Locci, Erbo Dong, Ferdinando Nicoletti, Alessandro Guidotti and Dennis R. Grayson
Affiliation:
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL
60612, USA
Keywords:
mGlu5 receptor, autism, GABA, glutamate, MTEP, synaptic plasticity, PI hydrolysis, striatum.
Abstract:
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.
