Chunk #20 — 3. Overview of Monogenic Mouse Models of ASDs — 3.2 Post-Transcriptional Protein Modifiers or Regulators: Fmr1, Tsc1/2, Ube3a, and Pten — 3.2.1 Fmr1 (Fragile X syndrome)
The enhanced mGluR-mediated LTD observed in Fmr1 knockouts (Huber et al., 2002) paved the way for the mGluR theory for FXS pathogenesis, which posits that FXS symptoms are caused by mGluR5 signaling leading to deregulated mRNA translation in the absence of FMRP (Bear et al., 2004). This theory has been supported by the effectiveness of genetic depletion of mGluR5 (Dölen et al., 2007) and mGluR5 negative allosteric modulators (e.g. CTEP; Michalon et al., 2012) in alleviating behavioral and synaptic abnormalities in Fmr1 knockout mice. While neither of these studies included analysis of repetitive behaviors or social interactions, negative allosteric modulation of mGluR5 decreased repetitive behaviors and increased sociability of a different mouse model of ASD: the BTBR inbred strain (Silverman et al., 2012). However, the mGluR5 signaling pathway is not the only molecular cascade that results in FMRP de-repression and subsequent dysregulated translation. For instance, the BDNF/TrkB signaling pathway converges with the mGluR5 pathway to initiate translation (reviewed in Castrén and Castrén, 2014; see Figure 1). It remains to be determined whether dysregulation of the BDNF/TrkB signaling pathway, the mGluR5
