5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

Matthew T. Reilly, Lauren C. Milner, Renee L. Shirley, John Jr Crabbe, Kari Buck

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is > 99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

Original languageEnglish (US)
Pages (from-to)124-131
Number of pages8
JournalBrain Research
Volume1198
DOIs
StatePublished - Mar 10 2008

Fingerprint

Receptor, Serotonin, 5-HT2C
Chromosomes, Human, Pair 4
Seizures
Central Nervous System
Genes
Alcohols
GABA-B Receptors
PDZ Domains
Serotonin 5-HT2 Receptor Antagonists
Pentylenetetrazole
Baclofen
GABA-A Receptors
Genetic Predisposition to Disease
Pharmaceutical Preparations
barbituric acid
Proteins

Keywords

  • Genetic
  • Mouse
  • MPDZ
  • MUPP1
  • Seizure
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice. / Reilly, Matthew T.; Milner, Lauren C.; Shirley, Renee L.; Crabbe, John Jr; Buck, Kari.

In: Brain Research, Vol. 1198, 10.03.2008, p. 124-131.

Research output: Contribution to journalArticle

@article{440b42911e3a4b2a998969640e627c7d,
title = "5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice",
abstract = "Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is > 99{\%} from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.",
keywords = "Genetic, Mouse, MPDZ, MUPP1, Seizure, Serotonin",
author = "Reilly, {Matthew T.} and Milner, {Lauren C.} and Shirley, {Renee L.} and Crabbe, {John Jr} and Kari Buck",
year = "2008",
month = "3",
day = "10",
doi = "10.1016/j.brainres.2008.01.024",
language = "English (US)",
volume = "1198",
pages = "124--131",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - 5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

AU - Reilly, Matthew T.

AU - Milner, Lauren C.

AU - Shirley, Renee L.

AU - Crabbe, John Jr

AU - Buck, Kari

PY - 2008/3/10

Y1 - 2008/3/10

N2 - Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is > 99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

AB - Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is > 99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

KW - Genetic

KW - Mouse

KW - MPDZ

KW - MUPP1

KW - Seizure

KW - Serotonin

UR - http://www.scopus.com/inward/record.url?scp=43049083994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43049083994&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2008.01.024

DO - 10.1016/j.brainres.2008.01.024

M3 - Article

C2 - 18262506

AN - SCOPUS:43049083994

VL - 1198

SP - 124

EP - 131

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -