Fragile X mental retardation protein (FMRP) is an
RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X
mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated
metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with
fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with
autism,
schizophrenia,
bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with
autism:
homer 1,
amyloid beta A4 precursor
protein (APP),
ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched
protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four
proteins in lateral cerebella of subjects with
schizophrenia,
bipolar disorder, and major depression and in frontal cortex of subjects with
schizophrenia and
bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120 kDa form of APP in subjects with
schizophrenia and
bipolar disorder; 2) reduced expression of 61 kDa and 33k Da forms of STEP in subjects with
schizophrenia; 3) reduced expression of 88 kDa form of APP in subjects with
bipolar disorder; and 3) trends for reduced expression of 88 kDa form of APP and
homer 1 in subjects with
schizophrenia and
bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with
bipolar disorder, and trends for increased RAC1 in subjects with
schizophrenia and major depression. Our results provide further evidence that
proteins involved in the FMRP-mGluR5 signaling pathway are altered in
schizophrenia and
mood disorders.