This mutant mouse strain carries a targeted mutation of the Hrh3, histamine receptor H3, gene, exhibit reduced activity levels, increase startle response and increased susceptibility to experimental allergic encephalomyelitis and cerebral malaria infection. These mutant mice may be useful in studies of pain perception, neuroinflammation, blood brain barrier integrity, and the regulation of histamine.
Wai-Ping Fung-Leung, Janssen Research & Development, L.L.C.
Histamine H3 receptors are found predominantly in the central nervous system, many are presynaptic in location, and are also expressed at lower levels in gastrointestinal, bronchial and cardiovascular tissues. Release of histamine, acetylcholine, glutamate, GABA, 5-HT, noradrenaline and dopamine neurotransmitters are regulated (inhibited) by the histamine H3 receptor. H3 receptors are able to form heterodimers with dopamine receptor D1 and D2. These mice carry a targeted mutation of the Hrh3, histamine receptor H3, gene, in which exon 1 and part of exon 2 have been replaced by a NEO cassette. Mice that are homozygous for the targeted mutation are viable and fertile. No gene product (mRNA or protein) is detected by Northern or RT-PCR analysis of brain tissue, and no functional activity is detected by radioligand binding assay of brain tissue. While homozygotes exhibit reduced levels of histamine in the cerebral cortex, levels of dopamine, norepinephrine and serotonin are unchanged. Homozygotes display decreased spontaneous locomotor activity and wheel-running behavior, as well as decreased sensitivity to thioperamide, methamphetamine and scopolamine. Mutant mice have increased startle response, reduced anxiety and enhanced spatial learning and memory (Barnes maze), with increased arginine vasopressin levels of the amygdala central and basolateral nuclei. Basal norepinephrine release levels from cardiac sympathetic nerve endings is approximately 60% higher than levels in wildtype controls. Experimentally induced ischemia results in 2 fold increase of norepinephrine overflow and more severe reperfusion arrhythmias. Mice deficient in histamine H3 receptors develop more severe experimental allergic encephalomyelitis (EAE), with increased neuroinflammation and blood brain barrier permeability. Experimentally induced cerebral malaria (Plasmodium berghei ANKA infection) is accelerated and more severe, with loss of blood brain barrier integrity, in homozygotes compared to wildtype controls. The antinociceptive effect of intrathecally administration of morphine is enhanced in homozygotes compared to wildtype controls.
A targeting vector designed by Drs. Wai-Ping Fung-Leung and Timothy W. Lovenberg (Johnson & Johnson Pharmaceutical Research and Development, San Diego, California) containing a NEO cassette was used to disrupt 0.7kb sequence including exon 1 and the 5' portion of exon 2. The construct was electroporated into 129P2/OlaHsd derived E14 embryonic stem (ES) cells. The resulting chimeric male animals were crossed to female C57BL/6J mice, and then backcrossed to C57BL/6J using a speed congenic method. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.
|Allele Name||targeted mutation 1, Timothy W Lovenberg|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Hrh3, histamine receptor H3|
|Strain of Origin||129P2/OlaHsd|
|Molecular Note||A neomycin selection cassette replaced a 0.7 kb fragment containing exon 1 and part of exon 2.|
When maintaining a live colony, these mice can be bred as homozygotes.
When using the B6.129P2-Hrh3tm1Twl/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #023433 in your Materials and Methods section.