Molecular Genetics Of Glutamate Function

Lipsky, Robert H.

Abstract

The subjects in this study were drawn from the Vietnam Head Injury Study registry, 92% of whom had a history of a penetrating head injury. Phase 3 (P3) has been modeled upon the Phase 2 (P2) Vietnam Head Injury Study. Of the 520 head-injured subjects that were assessed in P2, 484 are still alive, and 200 attended P3 of the study. Additionally, 20 patients identified in Phase 1 but that did not attend P2 were assessed. Of the original 80 control subjects without head injuries recruited in P2, 32 attended P3 and a further 27 were recruited for P3, through advertisements in veteran publications. Subjects were assessed over 5-7 days at the National Naval Medical Center in Bethesda, Maryland.? There were no significant differences between the head-injured and control subjects in terms of age at P3 testing, years of education or induction intelligence level (as measured by the Armed Forces Qualification Test; AFQT)? One genetic marker that was found to significantly predict overall change in AFQT score from P2 to P3 was GRIN2A: 8212 (F=4.033; p=0.020, df=2). All subjects with GRIN2A: 8212 were either heterozygous dominant (A1), heterozygous recessive (A20) or were homozygotes. An ANOVA procedure was carried out to see if each of these groups had an increased significance of decline compared to those without a GRIN2A: 8212 allele. Whilst there was a trend for dominant heterozygotes to have a greater level of decline in intelligence from P2 to P3 (mean=-11.714, sd=15.663) compared with recessive heterozygotes (mean=-9.071, sd=12.608) and homozygotes (mean=-8.519, sd=10.988), this did not reach significance. ? Again, the only genetic marker that was found to significantly predict overall change in AFQT score from preinjury to P3 was GRIN2A: 8212 (F=3.802; p=0.025, df=2). An ANOVA procedure was carried out to see if the those with a GRIN2A: 8212 allele showed a increased level of decline in intelligence from preinjury to P3. Again although there was a trend for dominant homozygotes to have a greater level of decline in intelligence from P2 to P3 (mean=-9.429, sd=22.849) compared with recessive homozygotes (mean=-8.021, sd=18.432) and heterozgotes (mean=-5.548, sd=18.205), this did not reach significance.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AA000325-08
• Application #: 7732118
• Support Year: 8
• Fiscal Year: 2008
• Total Cost: $339,602

Institution

• Name: National Institute on Alcohol Abuse and Alcoholism
• Country: United States

Publications

Tian, Feng; Hu, Xian-Zhang; Wu, Xuan et al. (2009) Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1. J Neurochem 109:1375-88

Roecklein, Kathryn A; Rohan, Kelly J; Duncan, Wallace C et al. (2009) A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder. J Affect Disord 114:279-85

Raymont, Vanessa; Greathouse, Amanda; Reding, Katherine et al. (2008) Demographic, structural and genetic predictors of late cognitive decline after penetrating head injury. Brain 131:543-58

Xu, K; Anderson, T R; Neyer, K M et al. (2007) Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence. Pharmacogenomics J 7:368-79

Paddock, Silvia; Laje, Gonzalo; Charney, Dennis et al. (2007) Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry 164:1181-8

Lipsky, R H; Jiang, X; Xu, K et al. (2005) Genomics and variation of ionotropic glutamate receptors: implications for neuroplasticity. Amino Acids 28:169-75

Wu, Xuan; Jiang, Xueying; Marini, Ann M et al. (2005) Delineating and understanding cerebellar neuroprotective pathways: potential implication for protecting the cortex. Ann N Y Acad Sci 1053:39-47

Zhu, Daming; Wu, Xuan; Strauss, Kenneth I et al. (2005) N-methyl-D-aspartate and TrkB receptors protect neurons against glutamate excitotoxicity through an extracellular signal-regulated kinase pathway. J Neurosci Res 80:104-13

Honse, Yumiko; Ren, Hong; Lipsky, Robert H et al. (2004) Sites in the fourth membrane-associated domain regulate alcohol sensitivity of the NMDA receptor. Neuropharmacology 46:647-54

Marini, Ann M; Jiang, Xueying; Wu, Xuan et al. (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: From genes to phenotype. Restor Neurol Neurosci 22:121-30