Functional studies in mouse models have demonstrated the role of the HDC gene in multiple facets of behavior, including some related to autism spectrum disorder. Both heterozygous and homozygous Hdc knockout mice showed increased motor stereotypic behavior after amphetamine administration compared to wildtype; stereotypic behavior was more marked in homozygous mice compared to heterozygous mice (Castellan Baldan et al., 2014). Agonists of the histamine H3 receptor were also shown to trigger stereotypic behavior in Hdc knockout mice (Rapanelli et al., 2017). Hdc knockout mice also exhibited decreased exploratory activity and increased anxiety in Dere et al., 2004. Interestingly, genetic studies have identified HDC as a candidate gene for Tourette's syndrome, a disorder with some similarities to ASD with regards to stereotypic and repetitive behavior (in the case of Tourette's syndrome, motor and vocal tics). A nonsense variant in HDC was found to segregate with Tourette's syndrome in a two-generation pedigree consisting of nine affected individuals in Ercan-Sencicek et al., 2010 (one of these individuals was subsequently reported to have high functioning autism in Castellan Baldan et al., 2014).
Molecular Function
This gene encodes a member of the group II decarboxylase family and forms a homodimer that converts L-histidine to histamine in a pyridoxal phosphate dependent manner. Histamine regulates several physiologic processes, including neurotransmission, gastric acid secretion,inflamation, and smooth muscle tone.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.
Hdc knockout mice exhibit decreased sensorimotor gating. Mutant mice also have elevated expression of the histamine H3 receptor in the striatum. Administration of amphetamine or H3 agonists (R-aminomethylhistamine (RAMH) and immepip) produced behavioral stereotypies in the KO mice. H3 agonist treatment increased intra-striatal dopamine and increased phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. The dorsal striatal activity is necessary and sufficient for the development of stereotypy.
References
Type
Title
Author, Year
Primary
Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The region of Hdc gene from intron 5 to exon 9 (2.4 kb) is replaced with a PGK promoter-neo resistant cassette, which results in a null allele of Hdc gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The region of Hdc gene from intron 5 to exon 9 (2.4 kb) is replaced with a PGK promoter-neo resistant cassette, which results in a null allele of Hdc gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice are injected with a single intraperitoneal (i.p.) dose of D-amphetamine (5 mg/kg in sterile saline to avoid saturating the response) 45 min before starting experiments. Wildtype mice with the same treatment are used as controls.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice are injected with a single intraperitoneal (i.p.) dose of D-amphetamine (8.5 mg/kg in sterile saline) before starting behavioral tests. Wildtype mice with the same treatment are used as controls.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Heterozygous
Mutation:
Hdc heterozygous knockout mice are injected with a single intraperitoneal (i.p.) dose of D-amphetamine (8.5 mg/kg in sterile saline) before starting behavioral tests. Wildtype mice with the same treatment are used as controls.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice are injected with a single intraperitoneal (i.p.) dose of D-amphetamine (10 mg/kg in sterile saline) before starting behavioral tests. Wildtype mice with the same treatment are used as controls.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Heterozygous
Mutation:
Hdc heterozygous knockout mice are injected with a single intraperitoneal (i.p.) dose of D-amphetamine (10 mg/kg in sterile saline) before starting behavioral tests. Wildtype mice with the same treatment are used as controls.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice are injected with immepip (20 mg/kg, i.p.), a H3R agonist, before behavioral tests.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice are injected with R-aminomethylhistamine (RAMH; 0, 5, 20, or 45 mg/kg, intraperitoneal (i.p.)), a histamine receptor H3 (H3R) specific agonist, before starting behavioral tests.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
Hdc homozygous knockout mice that have been backcrossed onto D1-DARPP32-Flag/D2-DARPP32-Myc BAC double transgenic mice are infused bilaterally into the striatum with three viral particles, i.e. AAV2-E-SARE-ERT2-CreERT2-PEST32, AAV8-hSyn-DIO-HA-KORD (Gi)-IRES-mCitrine, and AAV5-hSyn-DIO-hM3D (Gq)-mCherry3. Two weeks after virus infusion, mice are injected IP with 4-OH- tamoxifen together with either saline or 45 mg/kg RAMH (R-aminomethylhistamine, a H3R specific agonist), to allow activity-dependent cell tagging in active cells of the dorsal striatum. Behavioral analysis is initiated one week after cell tagging. Mice are injected with RAMH or saline, and/or other drugs 20 min before starting behavioral tests.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6; FVB
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A DREADD based chemogenetic multifactorial model. Hdc homozygous knockout mice that have been backcrossed onto D1-DARPP32-Flag/D2-DARPP32-Myc BAC double transgenic mice are infused bilaterally into the striatum with three viral particles, i.e. a vector encoding activity-dependent expression of tamoxifen-inducible Cre recombinase, a vector encoding neuronal specific expression of excitatory DREADD construct, and a vector encoding neuronal specific expression of inhibitory DREADD construct. Two weeks after virus infusion, mice are injected IP with 4-OH- tamoxifen together with either saline or 45 mg/kg RAMH (R-aminomethylhistamine, a H3R specific agonist), to allow activity-dependent cell tagging in active cells of the dorsal striatum. Behavioral analysis is initiated two weeks after cell tagging. Mice are injected with RAMH or saline, and clozapine-N-oxide (CNO, 5 mg/kg, i.p.) 20 min before starting behavioral tests.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57Bl/6; FVB
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source:
Description: Hdc nulls exhibit increasd levels of brain dopamine during the dark cycle, relative to the wildtype controls
Exp Paradigm: Liquid chromatography-mass spectrometry (lc-ms)
Description: Hdc nulls exhibit decreasd levels of brain histamine during the light and the dark cycles relative to the wildtype controls
Exp Paradigm: Liquid chromatography-mass spectrometry (lc-ms)
Description: Decreased levels of hrh2 specific ligand binding in the striatum of hdc knockout mice
Exp Paradigm: Radioligand binding studies: 25i-iodoaminopontidine
Description: Increased levels of hrh3 in the striatum of hdc knockout mice
Exp Paradigm: Radioligand binding studies: 3h-n-alpha-methylhistamine; in situ hybridization (ish): hrh3
Description: Decreased levels of histamine in the hypothalamus, striatum, and cortex of hdc null mice relative to wildtype controls
Exp Paradigm: High-performance liquid chromatography (hplc)
Description: Phosphorylation of riboprotein s6 (rps6) in the dorsal striatum is increased at baseline in hdc-ko mice
Exp Paradigm: Immunostaining: phosphorylated rps6
Description: Hdc null mice exhibit increased expression of fos in both striasomes and matrix, relative to wildtype sibling controls
Exp Paradigm: Immunohistochemistry: fos
Description: Hdc nulls exhibit decreased sensorimotor gating, on either daytime or nightime, relative to the wildtype controls
Exp Paradigm: Prepulse inhibition:
Description: Hdc nulls exhibit increased raclopride binding (a specific ligand to dopamine receptors d2 and d3) in substantia nigra relative to the wildtype controls
Exp Paradigm: Radioligand binding studies
Description: Hdc nulls exhibit decreased raclopride binding (a specific ligand to dopamine receptors d2 and d3) in dorsal striatum relative to the wildtype controls
Exp Paradigm: Radioligand binding studies
Description: Decreased levels of histamine in the hypothalamus, striatum, and cortex of hdc hets relative to wildtype controls
Exp Paradigm: High-performance liquid chromatography (hplc)
Description: Hdc hets exhibit increased raclopride binding (a specific ligand to dopamine receptors d2 and d3) in substantia nigra relative to the wildtype controls
Exp Paradigm: Radioligand binding studies
Description: Hdc hets exhibit decreased raclopride binding (a specific ligand to dopamine receptors d2 and d3) in dorsal striatum relative to the wildtype controls
Exp Paradigm: Radioligand binding studies
Description: Amphetamine treated hdc nulls exhibit decreased ambulatory activity relative to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Open field test
Description: Amphetamine treated hdc nulls exhibit increased stereotypy behavior relative to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Observation of repetitive behavior: the majority consisted of repetitive focused sniffing and orofacial movements
Description: Amphetamine treated hdc hets exhibit decreased ambulatory activity when comparing to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Open field test
Description: Amphetamine treated hdc nulls exhibit decreased ambulatory activity relative to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Open field test
Description: Amphetamine treated hdc hets exhibit decreased ambulatory activity when comparing to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Open field test
Description: Amphetamine treated hdc hets exhibit increased stereotypy behavior relative to the wildtype mice treated with the same amphetamine treatment
Exp Paradigm: Observation of repetitive behavior: the majority consisted of repetitive focused sniffing and orofacial movements
Description: The striatal da increases significantly in hdc-ko mice when challenged by ramh relative to controls
Exp Paradigm: High-performance liquid chromatography (hplc)
Description: Ribosomal protein s6 phosphorylation is increased by ramh treatment in both wt and ko animals
Exp Paradigm: Immunostaining: phosphorylated rps6
Description: Activating hm3dq dreadd channel in dorsal striatal cells increases stereotypy in the ramh-activated hdc ko mice
Exp Paradigm: Observation of repetitive behavior
