Genetic reduction of group 1 metabotropic glutamate receptors alters select behaviors in a mouse model for fragile X syndrome

Abstract

Introduction Genetic heterogeneity likely contributes to variability in the symptoms among individuals with fragile X syndrome (FXS). Studies in the Fmr1 knockout (KO) mouse model for FXS suggest that excessive signaling through group I metabotropic glutamate receptors (Gp1 mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role. Hence, Gp1 mGluRs may act as modifiers of FXS. Currently no studies have addressed whether manipulation of mGluR1 activity may alter Fmr1 KO behavioral responses, and only a few have reported the effects of mGluR5 manipulation. Therefore, the goals for this study were to extend our understanding of the effects of modulating Gp1 mGluR activity on Fmr1 KO behavioral responses. Methods The present study determined if genetically reducing mGluR1 or mGluR5 by 50% affects an extensive array of behaviors in the Fmr1 KO. Results Reduction of mGluR1 moderately decreased Fmr1 KO activity. Reduction of mGluR5 caused an analgesic response in the Fmr1 KO and decreased active social behavior. Modulation of either mGluR1 or mGluR5 did not significantly alter audiogenic seizures, anxiety- and perseverative-related responses, sensorimotor gating, memory, or motor responses. Conclusions Genetic reduction of mGluR1 or mGluR5 modified a few select Fmr1 KO behaviors, although these modifications appeared to be subtle in nature and/or limited to select behaviors. This may indicate that 50% reduction of either mGluR1 or mGluR5 is insufficient to produce behavioral changes, and therefore, these receptors may not be dominant modifiers of a number of Fmr1 KO behavioral phenotypes.

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test

“…Previous studies have shown either a partial or a full rescue of fragile X phenotypes by introducing a heterozygous deletion of the mGlu5 receptor in Fmr1 KO mice (Dolen et al, 2007;Thomas et al, 2011). In the present study, both genetic and pharmacological reductions of mGluR5 function led to a partial rescue of the social tube deficit.…”

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…Phenotypes in italics were used to show rescue but the actual defects (e.g., increased vs reduced) varied in different studies. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; PI3K = phosphoinositide 3-kinase; mTOR = mammalian target of rapamycin; ERK = extracellular regulated kinase; GSK3β = glycogen synthase kinase 3β; LTD = long-term depression; PPI = prepulse inhibition *Most studies show rescue of increased marble burying but at least 2 studies reported decreased burying [118,162]. † These behaviors in rodents are often considered to recapitulate autistic-like behavior in humans.…”

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

“…Of note, recent studies in the mouse model showed that chronic treatment with mGlu5 NAMs is necessary to improve memory deficits [120,121,129], suggesting that prolonged treatment in patients may also be beneficial. Notably, targeting mGlu5 seems to be more efficient in rescuing phenotypes in the FXS mouse model than targeting other G-coupled receptors that were also shown to be dysregulated in FXS [217], such as mGlu1 or muscarinic receptors M1 and M4 [118,131,[136][137][138].…”

The complex genetics in autism spectrum disorders

“…FMR1-deficient mice show increased locomotor activity in the open-field test, elevated anxiety levels in the mirror-chamber test, and impaired social interaction with unfamiliar partners in multiple tests [52][53][54][55][56]. Interestingly, the FXS-like behavior phenotypes in FMR1 KO mice were rescued by repressing the function of group 1 metabotropic glutamate receptors (Gp1 mGluRs).…”