mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

Abstract

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions.

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

“…This result may be of relevance to ASD as increased microglial numbers and activation has also been observed in the brains of individuals with ASD (Morgan et al, 2010;Suzuki et al, 2013;Vargas et al, 2005) and with cases utilised for our post-mortem study of mGluR5 being a subset of a cohort used in the study by Morgan et al (2010). Neurobehavioral changes in mGluR5 KO mice have also been observed and include hyperlocomotion and a lack of novelty seeking behaviour (Parkitna et al, 2013;Gray et al, 2009;Jew et al, 2013), behaviours that can be considered to be correlates of ASD symptomatology.…”

“…In addition, mGluR5 knockout (KO) mice also demonstrate hyperlocomotion and deficits in spatial working memory (Burrows et al, 2015;Gray et al, 2009;Jew et al, 2013), together with a lack of novelty-seeking behaviour (Parkitna et al, 2013) and decreased pre-pulse inhibition (Brody et al, 2004;Chen et al, 2010). These findings are of interest given that sensorimotor deficits are seen in individuals with ASD, including excessive movement (De Jong et al, 2011) together with spatial working memory deficits (Steele et al, 2007) and low novelty-seeking behaviours and reward dependence also seen in individuals with ASD (Anckarsater et al, 2006).…”

Relevance of the metabotropic glutamate receptor (mGluR5) in the regulation of NREM-REM sleep cycle and homeostasis: Evidence from mGluR5 (−/−) mice

“…Therefore, disturbance in cyclic transitions of sleep-wake states and homeostatic drive might contribute to the convergent behavioral and cognitive alterations, described in mice lacking global mGluR5 [33]. However, deletion of mGluR5 expression only in principal cortical glutamatergic neurons did not impair sensorimotor gating and several forms of learning and social interactions [52], which is encouraging and holds promise to the mGluR5 and cognition field of research. The present results outline the potential effects of mGluR5 blockade on the mechanism of sleep and warrant assessment of vigilance states when considering clinical trials with new mGluR5 drug class therapy.…”

Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders

“…20 Decreased mGluR5 protein expression has been successfully reported previously by breeding the mGluR5-LoxP mouse line to a protamine-driven Cre-recombinase line, 21 by viral injection of Cre, 33 and by pyramidal neuron-specific deletion using a Nex-Cre line. 34,35 In the Pv-Creline used here, recombination begins at around postnatal week 2, reaching a plateau by 6 weeks, as assessed by Beta-Gal expression. 12 We have assessed specificity of mGluR5 deletion in Pv + cells by using combined in-situ hybridization for mGluR5 and Pv immunostaining.…”

“…Interestingly, deletion of mGluR5 from pyramidal neurons was shown to decrease, not increase, repetitive behavior. 35 Therefore, in addition to domain-specific memory deficits, the mGluR5-dependent manifestation of compulsive-like behavior is specifically caused by loss of mGluR5 function in Pv + cells. In light of recent evidence suggesting that mGluR5 antagonism could be an effective therapeutic agent in the treatment of Fragile X syndrome, 70 our findings suggest that blockade of mGluR5 during critical developmental stages may have unintended consequences, potentially exacerbating features of those disorders.…”