GABA-gated chloride ion influx and receptor binding studies in C57BL6J and DBA2J mice

doi:10.1016/0006-8993(86)91531-3

Brain Research

Volume 399, Issue 2, 10 December 1986, Pages 374-378

https://doi.org/10.1016/0006-8993(86)91531-3 Get rights and content

Abstract

GABA-gated chloride ion influx was measured in brain ‘microsac’ preparations of young (20–22-day-old) and older (40–42-day-old) C57BL6J and DBA2J mice. The young DBA2J mice are susceptible to audiogenic seizures. GABA sensitivity was reduced in young DBA2J mice as compared to age-matched C57BL6J mice or older mice of either strain. Age and strain differences in ligand binding to GABA/benzodiazepine receptor complex and glutamate receptor could not account for this finding. These results provide evidence for a defect in GABA-gated chloride ion influx in audiogenic seizure-susceptible DBA2J mice.

References (31)

ChiuT.H. et al.
GABA receptor-mediated modulation of [³H]diazepam binding in rat cortex
Eur. J. Pharmacol.
(1979)
GraillotC. et al.
Modulation of α₁-andα₂-adrenoceptor binding sites in the brain of audiogenic seizure susceptible mice (DBA/2J)
Eur. J. Pharmacol.
(1985)
HattoriH. et al.
γ-Aminobutyric acid, benzodiazepine binding sites and γ-aminobutyric acid concentrations in epileptic E1 mouse brain
Eur. J. Pharmacol.
(1985)
ItoM. et al.
Displaceable binding of [³H]l-glutamic acid to non-receptor materials
Life Sci.
(1986)
JobeP.C. et al.
Neurotransmitter abnormalities as determinants of seizure susceptibility and intensity in the genetic models of epilepsy
Biochem. Pharmacol.
(1981)
MeldrumB.S. et al.
Antiepileptic actions of excitatory amino acid antagonists in the photosensitive baboon, Papio papio
Neurosci. Lett.
(1983)
NicollR.A. et al.
The effects of pentobarbital and related compounds on frog motor neurons
Brain Research
(1980)
RobertsonH.R.
Audiogenic seizures: increased benzodiazepine receptor binding in a susceptible strain of mice
Eur. J. Pharmacol.
(1980)
SchlesingerK. et al.
Genetics of audiogenic seizures: I. Relation to brain serotonin and norepinephrine in mice
Life Sci.
(1965)
SchulzD.W. et al.
Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions
Brain Research
(1981)

BurchT.P. et al.

Group-selective reagent modification of the benzodiazepine-γ-aminobutyric acid receptor-ionophore complex reveals that low-affinity γ-aminobutyric acid receptors stimulate benzodiazepine binding

Mol. Pharmacol.

(1983)

CandyJ.M. et al.

The postnatal development of the benzodiazepine receptor in the cerebral cortex and cerebellum of the rat

J. Neurochem.

(1979)

ChiuT.H. et al.

Kinetics of [³H]flunitrazepam binding to membrane-bound benzodiazepine receptors

Mol. Pharmacol.

(1982)

CroucherM.J. et al.

Anticonvulsant action of excitatory amino acid antagonists

Science

(1982)

EnnaS.J. et al.

Influences of ions, enzymes and detergents on γ-aminobutyric acid-receptor binding in synaptic membranes of rat brain

Mol. Pharmacol.

(1977)

Cited by (28)

Attenuating effects of melatonin on pilocarpine-induced seizures in rats
2002, Comparative Biochemistry and Physiology - C Toxicology and Pharmacology
Daily melatonin (10–50 mg/kg, i.p.) treatment at 08.30 h or 17.00 h for 1 week of female rats (2-months-old) increased the latency to the appearance of the first convulsion in the pilocarpine-induced seizure model. Other behavior parameters remained unaltered. The anticonvulsant effect of melatonin seemed to be more intense at the light–dark transition. Moreover, the effect of repeated melatonin treatment was also age-related, since it showed a lower threshold in 2-month-old than in 21-day-old rats, and the acute treatment was not efficient. [³H]N-methylscopolamine binding was unaltered in the hippocampus and striatum of adult rats after the association of melatonin and pilocarpine. While muscarinic binding was unaltered in adult rats, it increased in the hippocampus of young rats in the presence of melatonin (50 mg/kg) and pilocarpine, and did not change in the striatum. Melatonin partially recovered [³H]GABA binding in the hippocampus in the presence of pilocarpine-induced seizures, and intensified pilocarpine effects in the striatum of adult rats.
GABA(A) receptor α4 subunit in DBA/2J and C57BL/6J mice
1998, Brain Research Bulletin
GABA_A receptors are chloride channels in the brain activated by binding of γ-aminobutyric acid (GABA). Several important classes of drugs, including alcohol and certain antiepileptic drugs, modulate the actions of GABA. We report the sequence and expression of α4 subunits of GABA_A receptors in two inbred strains of mice, DBA/2J and C57BL/6J, which differ in susceptibility to seizures and to behavioral effects of alcohol. We find no differences between the two strains in cDNA sequence, or in levels of α4 mRNA in whole brains of the two strains at 21 days of age, when DBA/2J are most susceptible to audiogenic seizures. We also describe the pattern of developmental expression and brain regional distribution of this subunit in mice, finding the highest developmental expression at about 14 days of age in whole brains, and the highest regional levels in hippocampus and basal forebrain (including thalamus) in adults.
The α5 subunit of the murine type A GABA receptor
1998, Molecular Brain Research
GABA_A receptors in the brain convert binding of GABA (γ-aminobutyric acid) to inhibition by chloride currents. Several important classes of drugs, including benzodiazepines and alcohol, modulate these receptors, which have also been implicated in epilepsy. We describe the α5 subunit of GABA_A receptors in mice, comparing inbred DBA/2J mice, prone to juvenile audiogenic seizures, with seizure resistant C57BL/6J mice. We find no sequence differences between the strains, although there are several interesting amino acid differences from the rat. We also compare the expression of the α5 subunit in whole brains of DBA/2J mice to that in C57BL/6J mice at 21 days, the peak of the former's seizure susceptibility, again finding no significant difference. We further describe the pattern of expression of α5 mRNA during mouse brain development, with a peak at 3 days after birth, and among five brain regions in the adult mouse, with the highest levels in the hippocampus. Finally, we present preliminary evidence for rare alternative splicing of this subunit's message, in the N-terminal extracellular domain, to give a form not translatable into a functional protein.
The GABA(A) receptor γ<inf>1</inf>-subunit in seizure prone (DBA/2) and resistant (C57BL/6) mice
1998, Brain Research Bulletin
γ-Aminobutyric acid (GABA)_A receptors are the sites of action for many antiepileptic drugs such as benzodiazepines and barbiturates. We report the results of molecular cloning of the γ₁-subunit from seizure prone DBA/2J and resistant C57BL/6J inbred mice, and analyses of nucleotide sequences and expression of the γ₁-subunit messenger RNA (mRNA) in DBA/2 and C57BL/6 inbred mice. The mouse γ₁-subunit complementary DNA (cDNA) shares 98% similarity with that of the rat at the level of amino acid sequence. Northern blot hybridization indicates that the γ₁-subunit mRNA is expressed predominantly in areas other than the cerebral cortex and cerebellum and shows little change with postnatal development. No differences have been found for the subunit between DBA/2 and C57BL/6 mice either for nucleotide sequence or for level of expression of the subunit’s mRNA in whole brain by Northern blots at 3 weeks of age.
Mice deficient in lysosomal acid phosphatase develop lysosomal storage in the kidney and central nervous system
1997, Journal of Biological Chemistry
Lysosomal acid phosphatase (LAP) is a tartrate-sensitive enzyme with ubiquitous expression. Neither the physiological substrates nor the functional significance is known. Mice with a deficiency of LAP generated by targeted disruption of the LAP gene are fertile and develop normally. Microscopic examination of various peripheral organs revealed progredient lysosomal storage in podocytes and tubular epithelial cells of the kidney, with regionally different ultrastructural appearance of the stored material. Within the central nervous system, lysosomal storage was detected to a regionally different extent in microglia, ependymal cells, and astroglia concomitant with the development of a progressive astrogliosis and microglial activation. Whereas behavioral and neuromotor analyses were unable to distinguish between control and deficient mice, ∼7% of the deficient animals developed generalized seizures. From the age of 6 months onward, conspicuous alterations of bone structure became apparent, resulting in a kyphoscoliotic malformation of the lower thoracic vertebral column. We conclude from these findings that LAP has a unique function in only a subset of cells, where its deficiency causes the storage of a heterogeneously appearing material in lysosomes. The causal relationship of the enzyme defect to the clinical manifestations remains to be determined.
GABA<inf>A</inf> receptor β<inf>1</inf>, β<inf>2</inf>, and β<inf>3</inf> subunits: comparisons in DBA/2J and C57BL/6J mice
1995, BBA - Gene Structure and Expression
GABA_A receptors link binding of GABA (γ-aminobutyric acid) to inhibitory chloride flux in the brain. They are the site of action of several important classes of drugs, and have been implicated in animal models of epilepsy and in the actions of alcohol. We compare the sequence and expression of the β1, β2 and β3 subunits of GABA_A receptors in two inbred strains of mice, DBA/2J and C57BL/6J, which differ markedly in seizure susceptibility and in a variety of behaviors related to alcohol. Only the β3 3 subunit had strain differences in cDNA nucleotide sequence, which did not affect amino acid sequence but which did create restriction fragment length polymorphisms (RFLPs) potentially useful in gene mapping. We have also tested mouse β1 and β2 subunits for internal alternative splicing, detecting none.

View all citing articles on Scopus

: This study was supported by research Grants R01-NS16595 and R01-DA02194 from U.S. DHHS.

View full text

GABA-gated chloride ion influx and receptor binding studies in C57BL6J and DBA2J mice

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Biochem. Pharmacol.

Neurosci. Lett.

Brain Research

Eur. J. Pharmacol.

Life Sci.

Brain Research

Group-selective reagent modification of the benzodiazepine-γ-aminobutyric acid receptor-ionophore complex reveals that low-affinity γ-aminobutyric acid receptors stimulate benzodiazepine binding

Mol. Pharmacol.

The postnatal development of the benzodiazepine receptor in the cerebral cortex and cerebellum of the rat

J. Neurochem.

Kinetics of [3H]flunitrazepam binding to membrane-bound benzodiazepine receptors

Mol. Pharmacol.

Anticonvulsant action of excitatory amino acid antagonists

Science

Influences of ions, enzymes and detergents on γ-aminobutyric acid-receptor binding in synaptic membranes of rat brain

Mol. Pharmacol.

Kinetics of [³H]flunitrazepam binding to membrane-bound benzodiazepine receptors