Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior

Gregg E. Homanics, Timothy M. DeLorey, Leonard L. Firestone, Joseph J. Quinlan, Adrian Handforth, Neil L. Harrison, Matthew D. Krasowski, Caroline E M Rick, Esa R. Korpi, Riikka Mäkelä, Murray H. Brilliant, Nobuko Hagiwara, Carolyn Ferguson, Kimberly Snyder, Richard W. Olsen

Research output: Contribution to journalArticle

374 Citations (Scopus)

Abstract

γ-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The β3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a β3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of β3- deficient mice, and GABA(A)-R function is severely impaired. Most β3- deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. β3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the β3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. β3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.

Original languageEnglish (US)
Pages (from-to)4143-4148
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number8
DOIs
StatePublished - Apr 15 1997
Externally publishedYes

Fingerprint

Aminobutyrates
Cleft Palate
Epilepsy
gamma-Aminobutyric Acid
GABA-A Receptors
Brain
Mobility Limitation
Myoclonus
Gene Targeting
Infant Mortality
Body Size
Ataxia
Weaning
Gait
Synaptic Transmission
Tail
Spinal Cord
Seizures
Central Nervous System

Keywords

  • anesthesia
  • Angelman syndrome
  • benzodiazepine
  • gene targeting

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. / Homanics, Gregg E.; DeLorey, Timothy M.; Firestone, Leonard L.; Quinlan, Joseph J.; Handforth, Adrian; Harrison, Neil L.; Krasowski, Matthew D.; Rick, Caroline E M; Korpi, Esa R.; Mäkelä, Riikka; Brilliant, Murray H.; Hagiwara, Nobuko; Ferguson, Carolyn; Snyder, Kimberly; Olsen, Richard W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 8, 15.04.1997, p. 4143-4148.

Research output: Contribution to journalArticle

Homanics, GE, DeLorey, TM, Firestone, LL, Quinlan, JJ, Handforth, A, Harrison, NL, Krasowski, MD, Rick, CEM, Korpi, ER, Mäkelä, R, Brilliant, MH, Hagiwara, N, Ferguson, C, Snyder, K & Olsen, RW 1997, 'Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior', Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 8, pp. 4143-4148. https://doi.org/10.1073/pnas.94.8.4143
Homanics, Gregg E. ; DeLorey, Timothy M. ; Firestone, Leonard L. ; Quinlan, Joseph J. ; Handforth, Adrian ; Harrison, Neil L. ; Krasowski, Matthew D. ; Rick, Caroline E M ; Korpi, Esa R. ; Mäkelä, Riikka ; Brilliant, Murray H. ; Hagiwara, Nobuko ; Ferguson, Carolyn ; Snyder, Kimberly ; Olsen, Richard W. / Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 8. pp. 4143-4148.
@article{b883da1c01b64d968b4ed875c91726c1,
title = "Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior",
abstract = "γ-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The β3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a β3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of β3- deficient mice, and GABA(A)-R function is severely impaired. Most β3- deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. β3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the β3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. β3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.",
keywords = "anesthesia, Angelman syndrome, benzodiazepine, gene targeting",
author = "Homanics, {Gregg E.} and DeLorey, {Timothy M.} and Firestone, {Leonard L.} and Quinlan, {Joseph J.} and Adrian Handforth and Harrison, {Neil L.} and Krasowski, {Matthew D.} and Rick, {Caroline E M} and Korpi, {Esa R.} and Riikka M{\"a}kel{\"a} and Brilliant, {Murray H.} and Nobuko Hagiwara and Carolyn Ferguson and Kimberly Snyder and Olsen, {Richard W.}",
year = "1997",
month = "4",
day = "15",
doi = "10.1073/pnas.94.8.4143",
language = "English (US)",
volume = "94",
pages = "4143--4148",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "8",

}

TY - JOUR

T1 - Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior

AU - Homanics, Gregg E.

AU - DeLorey, Timothy M.

AU - Firestone, Leonard L.

AU - Quinlan, Joseph J.

AU - Handforth, Adrian

AU - Harrison, Neil L.

AU - Krasowski, Matthew D.

AU - Rick, Caroline E M

AU - Korpi, Esa R.

AU - Mäkelä, Riikka

AU - Brilliant, Murray H.

AU - Hagiwara, Nobuko

AU - Ferguson, Carolyn

AU - Snyder, Kimberly

AU - Olsen, Richard W.

PY - 1997/4/15

Y1 - 1997/4/15

N2 - γ-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The β3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a β3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of β3- deficient mice, and GABA(A)-R function is severely impaired. Most β3- deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. β3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the β3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. β3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.

AB - γ-Aminobutyric acid type A receptors (GABA(A)-Rs) mediate the bulk of rapid inhibitory synaptic transmission in the central nervous system. The β3 subunit is an essential component of the GABA(A)-R in many brain regions, especially during development, and is implicated in several pathophysiologic processes. We examined mice harboring a β3 gene inactivated by gene targeting. GABA(A)-R density is approximately halved in brain of β3- deficient mice, and GABA(A)-R function is severely impaired. Most β3- deficient mice die as neonates; some neonatal mortality, but not all, is accompanied by cleft palate. β3-deficient mice that survive are runted until weaning but achieve normal body size by adulthood, although with reduced life span. These mice are fertile but mothers fail to nurture offspring. Brain morphology is grossly normal, but a number of behaviors are abnormal, consistent with the widespread location of the β3 subunit. The mice are very hyperactive and hyperresponsive to human contact and other sensory stimuli, and often run continuously in tight circles. When held by the tail, they hold all paws in like a ball, which is frequently a sign of neurological impairment. They have difficulty swimming, walking on grids, and fall off platforms and rotarods, although they do not have a jerky gait. β3-deficient mice display frequent myoclonus and occasional epileptic seizures, documented by electroencephalographic recording. Hyperactivity, lack of coordination, and seizures are consistent with reduced presynaptic inhibition in spinal cord and impaired inhibition in higher cortical centers and/or pleiotropic developmental defects.

KW - anesthesia

KW - Angelman syndrome

KW - benzodiazepine

KW - gene targeting

UR - http://www.scopus.com/inward/record.url?scp=12644290240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12644290240&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.8.4143

DO - 10.1073/pnas.94.8.4143

M3 - Article

C2 - 9108119

AN - SCOPUS:12644290240

VL - 94

SP - 4143

EP - 4148

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 8

ER -