The Therapeutic Potential of mGlu3 Antagonism in Correcting Hippocampal Long‐term Depression Impairments in a Mouse Model of MECP2 Duplication Syndrome

Abstract

Precise levels of the transcriptional regulator Methyl CpG Binding Protein 2 (MeCP2) are known to be a key determinant for proper neurological function. Mutations in the MECP2 gene results in a disease known as Rett syndrome; in contrast, genetic duplication of MECP2 leads to a disorder known as MECP2 Duplication syndrome. The latter genetic neurodevelopmental disorder has a wide symptomology including stereotypy, seizures, cognitive deficits, and autism. In rodent models of MECP2 Duplication Syndrome in which MeCP2 is overexpressed, increases in glutamatergic synapse formation in hippocampal neurons occur, as well as impairments in hippocampal synaptic plasticity, a neurological phenomenon thought to be involved in memory and cognition. In accordance with this notion, MeCP2 overexpression causes memory and cognitive deficits in mice. Interestingly, the metabotropic glutamate receptor 3 (mGlu3) has been shown to be involved in regulating synaptic plasticity and cognitive behaviors in mice, and mGlu3 expression appears to correlate with MeCP2 expression levels in the brain. We hypothesized that that an upregulation of mGlu3 leads to an impairment in synaptic plasticity and cognitive deficits in MeCP2 overexpressing mice. To investigate the mechanisms by which MeCP2 overexpression induces neurophysiological impairments, a MeCP2‐Tg1 mouse model was used. Our results indicate that mGlu3 is upregulated the hippocampus of MeCP2‐Tg1 mice, correlating with an increase in MeCP2 protein expression. Electrophysiological experiments found that paired‐pulse facilitation was enhanced and input‐output intensity was reduced at the SC‐CA1 hippocampal synapse in the MeCP2‐Tg1 mice compared to wild‐type controls. Furthermore, (S)‐3,5‐Dihydroxyphenylglycine (DHPG) induced‐long term depression (LTD) was impaired in MeCP2‐Tg1 mice. Interestingly, an mGlu3 negative allosteric modulator, VU0650786, was capable of normalizing DHPG‐induced LTD to the level of that observed in wild‐type controls. These results suggest that overexpression of mGlu3 may contribute to synaptic plasticity impairments within the hippocampus of MeCP2‐Tg1 mice. Future experiments are aimed at elucidating behavioral correlates of these neurophysiological abnormalities and their underlying mechanisms.Support or Funding InformationT32NS007491 (BJS), rettsyndrome.org postdoctoral fellowship (RGG), Weatherstone predoctoral fellowship (BKS), T32 GM07628 (NF), R01 MH099269 (KAE), U54 MH084659 (CWL), R01 NS031373 (PJC), R21 MH102548 (CMN), Autism Speaks Treatment Award (CMN).