Figure 5

Reduction of FMRP expression has multiple consequences. In the absence or with reductions of FMRP, mGluR5-mediated signaling and protein synthesis is accelerated, resulting in increased expression of RAC1, APP, and STEP. Increased RAC1 and APP results in altered dendritic morphology, including presence of increased dendritic spines with a long, immature appearance. Increased STEP activity dephosphorylates multiple targets, including AMPA receptors and NMDA receptors, resulting in receptor internalization and altered synaptic transmission. Reduced homer 1 expression, reduces homer 1-mGluR5 interactions, facilitating long term depression. Reduced FMRP also results in reduced expression of GABA_A and GABA_B receptor subunits, resulting in impaired GABAergic signaling. Reduced FMRP expression may also impact Reelin expression causing further effects on synaptic transmission. The overall effect of these changes is impaired synaptic transmission and ultimately the cognitive and behavioral deficits associated with autism. FMRP, fragile X mental retardation protein; mGluR5, metabotropic glutamate receptor 5; RAC1, Ras-related C3 botulinum toxin substrate 1; amyloid beta A4 precursor protein; STEP, striatal-enriched protein tyrosine phosphatase; AMPA, 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid; NDMA, N-methyl-D-aspartate; GABA, gamma aminobutyric acid.