Potential pleiotropic effects of Mpdz on vulnerability to seizures.

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.

• Authors: C Fehr, R L Shirley, P Metten, A E K Kosobud, J K Belknap, J C Crabbe, K J Buck
• Journal: Genes, brain, and behavior (Genes Brain Behav) Vol. 3 Issue 1 Pg. 8-19 (Feb 2004) ISSN: 1601-1848 [Print] England
• PMID: 14960011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Convulsants
• Membrane Proteins
• Mpdz protein, mouse
• Ethanol
• Glutamic Acid
• gamma-Aminobutyric Acid
• Pentobarbital

Topics

• Amino Acid Motifs (genetics)
• Animals
• Carrier Proteins (genetics)
• Chromosome Mapping
• Convulsants
• Ethanol
• Female
• Genetic Predisposition to Disease
• Glutamic Acid (metabolism)
• Male
• Membrane Proteins
• Mice
• Mice, Inbred Strains
• Pentobarbital
• Phenotype
• Quantitative Trait, Heritable
• Seizures (chemically induced, genetics)
• Species Specificity
• Substance Withdrawal Syndrome (genetics)
• gamma-Aminobutyric Acid (metabolism)