Potential pleiotropic effects of Mpdz on vulnerability to seizures

C. Fehr, R. L. Shirley, P. Metten, Ann Kosobud, J. K. Belknap, J. C. Crabbet, Kari J. Buck

Research output: Contribution to journalArticle

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Abstract

We previously mapped quantitative trait loci (QTL) responsible for approximately 26% of the genetic variance in acute alcohol and barbiturate (i.e., pentobarbital) withdrawal convulsion liability to a < 1 cM (1.8 Mb) interval of mouse chromosome 4. To date, Mpdz, which encodes the multiple PSD95/DLG/ZO-1 (PDZ) domain protein (MPDZ), is the only gene within the interval shown to have allelic variants that differ in coding sequence and/or expression, making it a strong candidate gene for the QTL. Previous work indicates that Mpdz haplotypes in standard mouse strains encode distinct protein variants (MPDZ1-3), and that MPDZ status is genetically correlated with severity of withdrawal from alcohol and pentobarbital. Here, we report that MPDZ status cosegregates with withdrawal convulsion severity in lines of mice selectively bred for phenotypic differences in severity of acute withdrawal from alcohol [i.e., High Alcohol Withdrawal (HAW) and Low Alcohol Withdrawal (LAW) lines] or pentobarbital [High Pentobarbital Withdrawal (HPW) and Low Pentobarbital Withdrawal (LPW) lines]. These analyses confirm that MPDZ status is associated with severity of alcohol and pentobarbital withdrawal convulsions. Using a panel of standard inbred strains of mice, we assessed the association between MPDZ status with seizures induced by nine chemiconvulsants. Our results show that MPDZ status is genetically correlated with seizure sensitivity to pentylenetetrazol, kainate and other chemiconvulsants. Our results provide evidence that Mpdz may have pleiotropic effects on multiple seizure phenotypes, including seizures associated with withdrawal from two classes of central nervous system (CNS) depressants and sensitivity to specific chemiconvulsants that affect glutaminergic and GABAergic neurotransmission.

Original languageEnglish
Pages (from-to)8-19
Number of pages12
JournalGenes, Brain and Behavior
Volume3
Issue number1
DOIs
StatePublished - Feb 2004

Fingerprint

Pentobarbital
Seizures
Alcohols
Quantitative Trait Loci
Central Nervous System Depressants
Pentylenetetrazole
Chromosomes, Human, Pair 4
Inbred Strains Mice
Kainic Acid
Synaptic Transmission
Haplotypes
Phenotype
Genes
Proteins

Keywords

  • Convulsion
  • DMCM
  • Ethanol
  • GABA
  • Genetics
  • Glutamate
  • Kainate
  • Pentobarbital
  • Pentylenetetrazol
  • Quantitative trait loci
  • Withdrawal

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics

Cite this

Fehr, C., Shirley, R. L., Metten, P., Kosobud, A., Belknap, J. K., Crabbet, J. C., & Buck, K. J. (2004). Potential pleiotropic effects of Mpdz on vulnerability to seizures. Genes, Brain and Behavior, 3(1), 8-19. https://doi.org/10.1111/j.1601-183X.2004.00035.x

Potential pleiotropic effects of Mpdz on vulnerability to seizures. / Fehr, C.; Shirley, R. L.; Metten, P.; Kosobud, Ann; Belknap, J. K.; Crabbet, J. C.; Buck, Kari J.

In: Genes, Brain and Behavior, Vol. 3, No. 1, 02.2004, p. 8-19.

Research output: Contribution to journalArticle

Fehr, C, Shirley, RL, Metten, P, Kosobud, A, Belknap, JK, Crabbet, JC & Buck, KJ 2004, 'Potential pleiotropic effects of Mpdz on vulnerability to seizures', Genes, Brain and Behavior, vol. 3, no. 1, pp. 8-19. https://doi.org/10.1111/j.1601-183X.2004.00035.x
Fehr, C. ; Shirley, R. L. ; Metten, P. ; Kosobud, Ann ; Belknap, J. K. ; Crabbet, J. C. ; Buck, Kari J. / Potential pleiotropic effects of Mpdz on vulnerability to seizures. In: Genes, Brain and Behavior. 2004 ; Vol. 3, No. 1. pp. 8-19.
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