Exploration of group II metabotropic glutamate receptor modulation in mouse models of Rett syndrome and MECP2 Duplication syndrome

Abstract

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2). Several clinical and preclinical phenotypes, however, are shared between these disorders. Modulation of MeCP2 levels has recently emerged as a potential treatment option for both of these diseases. However, toxicity concerns remain with these approaches. Here, we focus on pharmacologically modulating the group II metabotropic glutamate receptors (mGlu), mGlu₂ and mGlu₃, which are two downstream targets of MeCP2 that are bidirectionally affected in expression in RTT patients and mice (Mecp2^Null/+) versus an MDS mouse model (MECP2^Tg1/o). Mecp2^Null/+ and MECP2^Tg1/o animals also exhibit contrasting phenotypes in trace fear acquisition, a form of temporal associative learning and memory, with trace fear deficiency observed in Mecp2^Null/+ mice and abnormally enhanced trace fear acquisition in MECP2^Tg1/o animals. In Mecp2^Null/+ mice, treatment with the mGlu_2/3 agonist LY379268 reverses the deficit in trace fear acquisition, and mGlu_2/3 antagonism with LY341495 normalizes the abnormal trace fear learning and memory phenotype in MECP2^Tg1/o mice. Altogether, these data highlight the role of group II mGlu receptors in RTT and MDS and demonstrate that both mGlu₂ and mGlu₃ may be potential therapeutic targets for these disorders.

Keywords: MECP2; MECP2 duplication syndrome; Rett syndrome; Trace fear; mGlu(2); mGlu(3).