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The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10-day-old male rats revealed a high and selective uptake in the pineal gland at 30minutes to 24hours after C-14-L-BMAA administration (0.68mg/kg). Primary pinealocyte cultures exposed to 0.05-3mmol/L BMAA showed a 57%-93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2weeks after BMAA administration (460mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA-induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress.

While the functional disconnectivity hypothesis of schizophrenia has been the subject of much study, very little is known about the contribution of individual genotypes to connectivity between brain regions in either schizophrenia patients or in healthy controls. In this study, we obtained diffusion tensor imaging (DTI) maps and genome-wide SNP data from 74 cases and 87 age- and gender-matched controls. Correlations were performed between loading coefficients obtained from fractional anisotropy (FA) values in networks of regions representing 6 maximally independent components and 134 SNPs in genes that have been found to be important in myelination and/or schizophrenia. By using independent component analysis (ICA) to analyze the FA data we move beyond single voxels (voxel based morphometry) to a source based morphometry. In doing so, we can obtain networks of FA values that covary in a similar way among subjects, and we can study the relationship between these networks and genotype. We report one SNP located in the intronic region of the metabotropic glutamate receptor 3 gene GRM3 that showed a significant correlation with connectivity in patients but not in controls (p<1.0x10-4). This SNP, rs7808623, has not been previously shown to be associated with schizophrenia, although association has been shown with several SNPs in GRM3.

While the functional disconnectivity hypothesis of schizophrenia has been the subject of much study, very little is known about the contribution of individual genotypes to connectivity between brain regions in either schizophrenia patients or in healthy controls. In this study, we obtained diffusion tensor imaging (DTI) maps and genome-wide SNP data from 74 cases and 87 age- and gender-matched controls. Correlations were performed between loading coefficients obtained from fractional anisotropy (FA) values in networks of regions representing 6 maximally independent components and 134 SNPs in genes that have been found to be important in myelination and/or schizophrenia. By using independent component analysis (ICA) to analyze the FA data we move beyond single voxels (voxel based morphometry) to a source based morphometry. In doing so, we can obtain networks of FA values that covary in a similar way among subjects, and we can study the relationship between these networks and genotype. We report one SNP located in the intronic region of the metabotropic glutamate receptor 3 gene GRM3 that showed a significant correlation with connectivity in patients but not in controls (p<1.0x10-4). This SNP, rs7808623, has not been previously shown to be associated with schizophrenia, although association has been shown with several SNPs in GRM3.