MDGA1-deficiency attenuates prepulse inhibition with alterations of dopamine and serotonin metabolism : An ex vivo HPLC-ECD analysis

AbstractMDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor) has recently been linked to schizophrenia and bipolar disorder. Dysregulation of dopamine (DA) and serotonin (5-HT) systems has long been associated with schizophrenia and other neuropsychiatric disorders. Here, we measured prepulse inhibition (PPI) of the startle response and ex vivo tissue content of monoamines and their metabolites in the frontal cortex, striatum and hippocampus of Mdga1 homozygous (Mdga1-KO), Mdga1 heterozygous (Mdga1-HT) and wild-type (WT) male mice. We found that Mdga1-KO mice exhibited statistically significant impairment of PPI, and had higher levels of homovanillic acid in all three brain regions studied compared with Mdga1-HT and WT mice (P < 0.05), while levels of norepinephrine, DA and its metabolites 3,4-dihydroxyphenylacetic acid and 3-methoxytyramine remained unchanged. Mdga1-KO mice also had a lower 5-hydroxyindoleacetic acid level in the striatum (P < 0.05) compared with WT mice. 5-HT levels remained unchanged with the exception of a significant increase in the level in the cortex. These data are the first evidence suggesting that MDGA1 deficiency leads to a pronounced deficit in PPI and plays an important role in perturbation of DA and 5-HT metabolism in mouse brain; such changes may contribute to a range of neuropsychiatric disorders.

Abstract MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor) has recently been linked to schizophrenia and bipolar disorder. Dysregulation of dopamine (DA) and serotonin (5-HT) systems has long been associated with schizophrenia and other neuropsychiatric disorders. Here, we measured prepulse inhibition (PPI) of the startle response and ex vivo tissue content of monoamines and their metabolites in the frontal cortex, striatum and hippocampus of Mdga1 homozygous (Mdga1-KO), Mdga1 heterozygous (Mdga1-HT) and wild-type (WT) male mice. We found that Mdga1-KO mice exhibited statistically significant impairment of PPI, and had higher levels of homovanillic acid in all three brain regions studied compared with Mdga1-HT and WT mice (P < 0.05), while levels of norepinephrine, DA and its metabolites 3,4-dihydroxyphenylacetic acid and 3-methoxytyramine remained unchanged. Mdga1-KO mice also had a lower 5-hydroxyindoleacetic acid level in the striatum (P < 0.05) compared with WT mice. 5-HT levels remained unchanged with the exception of a significant increase in the level in the cortex. These data are the first evidence suggesting that MDGA1 deficiency leads to a pronounced deficit in PPI and plays an important role in perturbation of DA and 5-HT metabolism in mouse brain; such changes may contribute to a range of neuropsychiatric disorders.