The Role of mGlu7 in Hippocampal Synaptic Plasticity: Implications for Novel Therapeutics for Rett Syndrome

Abstract

Of the eight metabotropic glutamate (mGlu) receptor subtypes, only metabotropic glutamate receptor 7 (mGlu7) is expressed presynaptically at the Schaffer Collateral (SC)-CA1 synapse in the hippocampus in adult animals. To date, a lack of mGlu7-selective pharmacological tools has hampered direct investigation of its role in the regulation of neurotransmission. We have used a novel, selective mGlu7 negative allosteric modulator (NAM), ADX71743, and a newly described group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL6/J male mice. We have found that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of long term potentiation (LTP) at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders. Rett Syndrome is a neurodevelopmental disorder caused by mutations in the Methyl CpG Binding Protein 2 (MECP2) gene. The cognitive impairments seen in models of the disorder correlate with deficits in LTP at the SC-CA1 synapse in the hippocampus. As we have previously shown that mGlu7 is the only mGlu receptor expressed presynaptically at SC-CA1 synapses and its activation is necessary for induction of LTP, we sought to determine if alterations in mGlu7 function underlie the synaptic plasticity deficits observed in Rett syndrome model mice. Here, we report that MECP2 binds to the GRM7 promoter and positively regulates mGlu7 mRNA transcription. When MECP2 function is lost in both rodents and humans, mGlu7 protein levels are dramatically reduced. In Rett syndrome mice, these reductions result in a loss of mGlu7-mediated regulation of neurotransmission; excitingly, positive allosteric modulators rescue LTP and reverse deficits in contextual fear memory. These data suggest that positive modulation of mGlu7 may serve as a novel therapeutic approach for the cognitive disruptions characteristic of Rett syndrome.