| 1 | PLoS Biol. 2007 Nov 5: e297 |
|---|---|
| PMID | 18001149 |
| Title | Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. |
| Abstract | Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was FABP7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. FABP7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported FABP7 as a potential PPI-QTL gene, particularly in male mice. Disruption of FABP7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | PLoS Biol. 2007 Nov 5: e297 |
| PMID | 18001149 |
| Title | Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. |
| Abstract | Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was FABP7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. FABP7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported FABP7 as a potential PPI-QTL gene, particularly in male mice. Disruption of FABP7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | PLoS ONE 2009 -1 4: e5085 |
| PMID | 19352438 |
| Title | Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses. |
| Abstract | Prepulse inhibition (PPI) is a compelling endophenotype (biological markers) for mental disorders including schizophrenia. In a previous study, we identified FABP7, a fatty acid binding protein 7 as one of the genes controlling PPI in mice and showed that this gene was associated with schizophrenia. We also demonstrated that disrupting FABP7 dampened hippocampal neurogenesis. In this study, we examined a link between neurogenesis and PPI using different animal models and exploring the possibility of postnatal manipulation of neurogenesis affecting PPI, since gene-deficient mice show biological disturbances from prenatal stages. In parallel, we tested the potential for dietary polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and/or docosahexaenoic acid (DHA), to promote neurogenesis and improve PPI. PUFAs are ligands for Fabp members and are abundantly expressed in neural stem/progenitor cells in the hippocampus. Our results are: (1) an independent model animal, Pax6 (+/-) rats, exhibited PPI deficits along with impaired postnatal neurogenesis; (2) methylazoxymethanol acetate (an anti-proliferative drug) elicited decreased neurogenesis even in postnatal period, and PPI defects in young adult rats (10 weeks) when the drug was given at the juvenile stage (4-5 weeks); (3) administering ARA for 4 weeks after birth promoted neurogenesis in wild type rats; (4) raising Pax6 (+/-) pups on an ARA-containing diet enhanced neurogenesis and partially improved PPI in adult animals. These results suggest the potential benefit of ARA in ameliorating PPI deficits relevant to psychiatric disorders and suggest that the effect may be correlated with augmented postnatal neurogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J. Hum. Genet. 2010 Feb 55: 127-30 |
| PMID | 20057506 |
| Title | Polymorphism screening of brain-expressed FABP7, 5 and 3 genes and association studies in autism and schizophrenia in Japanese subjects. |
| Abstract | Fatty acid-binding protein (FABP) gene family encode fatty acid-binding proteins and consist of at least 12 members, of which FABP7, 5 and 3 are expressed in the brain. We previously showed that FABP7 is associated with schizophrenia and bipolar disorder. Recently, genetic overlap between autism and schizophrenia has been reported. Therefore, in this study, we set out to examine the possible roles of brain-expressed FABPs in autism, focusing primarily on potentially functional polymorphisms (that is, missense polymorphisms). First, we resequenced the three genes using 285 autism samples. We identified 13 polymorphisms, of which 7 are novel. Of the novel single-nucleotide polymorphisms (SNPs), two are missense mutations, namely, 376G>C (Val126Leu) in FABP7 and 340G>C (Gly114Arg) in FABP5. Second, we tested for the genetic association of four missense SNPs with autism and schizophrenia, but failed to detect significant results. Finally, as a web-based algorithm predicts that the 8A>G (Asp3Gly; rs17848124) in FABP3 is 'probably damaging', we estimated the possible impact of this SNP, and found that the loss of charge and salt bridge, caused by the Asp3-to-Gly3, may affect stability of the FABP3 protein. Future searches for associated phenotypes with missense SNPs using larger samples are highly warranted. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Brain Nerve 2010 Dec 62: 1315-22 |
| PMID | 21139184 |
| Title | [Molecular mechanism and mental function of postnatal neurogenesis]. |
| Abstract | Postnatal neurogenesis has been observed in two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, among vertebrates including human. Accumulating evidence has indicated the molecular mechanisms commonly underlying embryonic and adult neurogenesis. Genetic factors essential for neural development, i.e., Pax6, FABP7, Sox2, Wnt3, Notch1, etc., are also expressed in adult neurogenic regions. Adult neurogenesis, however, is distinct from embryonic neurogenesis in that the former is activity dependent; environmental stimulation modulates the entire processes of adult neurogenesis. In the hippocampus, physical exercise and cognitive stimuli robustly increase the proliferation of precursor cells, whereas physical/psychosocial stress decreases the proliferation of newborn neurons. Thus, adult neurogenesis is intriguingly regulated by several genetic and environmental factors. Reduction in hippocampal neurogenesis during the infantile and adult stages has been observed in some animal models of mental illness such as schizophrenia and major depression, implicating that postnatal neurogenesis may contribute to a part of the symptoms of mental illness. In this review, we describe the molecular mechanisms and functional significance of postnatal neurogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Mar 153B: 484-93 |
| PMID | 19554614 |
| Title | Association analyses between brain-expressed fatty-acid binding protein (FABP) genes and schizophrenia and bipolar disorder. |
| Abstract | Deficits in prepulse inhibition (PPI) are a biological marker for psychiatric illnesses such as schizophrenia and bipolar disorder. To unravel PPI-controlling mechanisms, we previously performed quantitative trait loci (QTL) analysis in mice, and identified FABP7, that encodes a brain-type fatty acid binding protein (Fabp), as a causative gene. In that study, human FABP7 showed genetic association with schizophrenia. FABPs constitute a gene family, of which members FABP5 and FABP3 are also expressed in the brain. These FABP proteins are molecular chaperons for polyunsaturated fatty acids (PUFAs) such as arachidonic and docosahexaenoic acids. Additionally, the involvement of PUFAs has been documented in the pathophysiology of schizophrenia and mood disorders. Therefore in this study, we examined the genetic roles of FABP5 and 3 in schizophrenia (N = 1,900 in combination with controls) and FABP7, 5, and 3 in bipolar disorder (N = 1,762 in the case-control set). Three single nucleotide polymorphisms (SNPs) from FABP7 showed nominal association with bipolar disorder, and haplotypes of the same gene showed empirical associations with bipolar disorder even after correction of multiple testing. We could not perform association studies on FABP5, due to the lack of informative SNPs. FABP3 displayed no association with either disease. Each FABP is relatively small and it is assumed that there are multiple regulatory elements that control gene expression. Therefore, future identification of unknown regulatory elements will be necessary to make a more detailed analysis of their genetic contribution to mental illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: FABP7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Hum. Mol. Genet. 2014 Dec 23: 6495-511 |
| PMID | 25027319 |
| Title | Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies. |
| Abstract | Disturbances of lipid metabolism have been implicated in psychiatric illnesses. We previously reported an association between the gene for fatty acid binding protein 7 (FABP7) and schizophrenia. Furthermore, we identified and reported several rare non-synonymous polymorphisms of the brain-expressed genes FABP3, FABP5 and FABP7 from schizophrenia and autism spectrum disorder (ASD), diseases known to part share genetic architecture. Here, we conducted further studies to better understand the contribution these genes make to the pathogenesis of schizophrenia and ASD. In postmortem brains, we detected altered mRNA expression levels of FABP5 in schizophrenia, and of FABP7 in ASD and altered FABP5 in peripheral lymphocytes. Using a patient cohort, comprehensive mutation screening identified six missense and two frameshift variants from the three FABP genes. The two frameshift proteins, FABP3 E132fs and FABP7 N80fs, formed cellular aggregates and were unstable when expressed in cultured cells. The four missense mutants with predicted possible damaging outcomes showed no changes in intracellular localization. Examining ligand binding properties, FABP7 S86G and FABP7 V126L lost their preference for docosahexaenoic acid to linoleic acid. Finally, mice deficient in Fabp3, Fabp5 and FABP7 were evaluated in a systematic behavioral test battery. The Fabp3 knockout (KO) mice showed decreased social memory and novelty seeking, and FABP7 KO mice displayed hyperactive and anxiety-related phenotypes, while Fabp5 KO mice showed no apparent phenotypes. In conclusion, disturbances in brain-expressed FABPs could represent an underlying disease mechanism in a proportion of schizophrenia and ASD sufferers. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Front Behav Neurosci 2014 -1 8: 110 |
| PMID | 24765068 |
| Title | Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype. |
| Abstract | The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (FABP7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia and BPD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Neurosci. Res. 2016 Jan 102: 47-55 |
| PMID | 25205626 |
| Title | Fatty acid binding proteins and the nervous system: Their impact on mental conditions. |
| Abstract | The brain is rich in lipid and fatty molecules. In this review article, we focus on fatty acid binding proteins (Fabps) that bind to fatty acids such as arachidonic acid and docosahexianoic acid and transfer these lipid ligands within the cytoplasm. Among Fabp family molecules, Fabp3, Fabp5, and FABP7 are specifically localized in neural stem/progenitor cells, neurons and glia in a cell-type specific manner. Quantitative trait locus analysis has revealed that FABP7 is related with performance of prepulse inhibition (PPI) that is used as an endophenotype of psychiatric diseases such as schizophrenia. Fabp5 and FABP7 play important roles on neurogenesis and differentially regulate acoustic startle response and PPI. However, other behavior performances including spatial memory, anxiety-like behavior, and diurnal changes in general activity were not different in mice deficient for FABP7 or Fabp5. Considering the importance of fatty acids in neurogenesis, we would like to emphasize that lipid nutrition and its dynamism via Fabps play significant roles in mental conditions. This might provide a good example of how nutritional environment can affect psychiatric conditions at the molecular level. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Schizophr. Res. 2016 Mar 171: 225-32 |
| PMID | 26792082 |
| Title | Fatty acid composition and fatty acid binding protein expression in the postmortem frontal cortex of patients with schizophrenia: A case-control study. |
| Abstract | Abnormal levels of n-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), have been found in the postmortem frontal cortex, particularly the orbitofrontal cortex, of patients with schizophrenia. Altered mRNA expression of fatty acid binding protein (FABP) 5 and FABP7 has likewise been reported. This study investigated whether PUFAs in the frontal cortex [Brodmann area (BA) 8] and mRNA expression of FABP3, 5, and 7 were different between patients with schizophrenia (n=95) and unaffected controls (n=93). In contrast to previous studies, no significant differences were found in DHA between the groups. Although arachidonic acid (AA) levels were significantly decreased in the schizophrenia group, no association was found between AA and schizophrenia on logistic regression analysis. Only FABP3 expression was significantly lower in the schizophrenia group than in the control group. Significant inverse associations were seen between only two saturated fatty acids, behenic acid and lignoceric acid, and FABP3 expression. We found no evidence that major PUFA levels in BA8 are involved in the etiology of schizophrenia. Although FABP3 expression was not correlated with any of the major PUFAs, it might play a novel role in the pathology of BA8 in a subset of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Glia 2016 Jan 64: 48-62 |
| PMID | 26296243 |
| Title | Astrocyte-expressed FABP7 regulates dendritic morphology and excitatory synaptic function of cortical neurons. |
| Abstract | Fatty acid binding protein 7 (FABP7) expressed by astrocytes in developing and mature brains is involved in uptake and transportation of fatty acids, signal transduction, and gene transcription. FABP7 knockout (FABP7 KO) mice show behavioral phenotypes reminiscent of human neuropsychiatric disorders such as schizophrenia. However, direct evidence showing how FABP7 deficiency in astrocytes leads to altered brain function is lacking. Here, we examined neuronal dendritic morphology and synaptic plasticity in medial prefrontal cortex (mPFC) of FABP7 KO mice and in primary cortical neuronal cultures. Golgi staining of cortical pyramidal neurons in FABP7 KO mice revealed aberrant dendritic morphology and decreased spine density compared with those in wild-type (WT) mice. Aberrant dendritic morphology was also observed in primary cortical neurons co-cultured with FABP7-deficient astrocytes and neurons cultured in FABP7 KO astrocyte-conditioned medium. Excitatory synapse number was decreased in mPFC of FABP7 KO mice and in neurons co-cultured with FABP7 KO astrocytes. Accordingly, whole-cell voltage-clamp recording in brain slices from pyramidal cells in the mPFC showed that both amplitude and frequency of action potential-independent miniature excitatory postsynaptic currents (mEPSCs) were decreased in FABP7 KO mice. Moreover, transplantation of WT astrocytes into the mPFC of FABP7 KO mice partially attenuated behavioral impairments. Collectively, these results suggest that astrocytic FABP7 is important for dendritic arbor growth, neuronal excitatory synapse formation, and synaptic transmission, and provide new insights linking FABP7, lipid homeostasis, and neuropsychiatric disorders, leading to novel therapeutic interventions. |
| SCZ Keywords | schizophrenia, schizophrenic |