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Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 241)

Abstract

While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relationship of abnormalities in neurotransmitter HA to human disease has been slower to emerge. New insight came with the 2010 description of a rare nonsense mutation in the biosynthetic enzyme histidine decarboxylase (Hdc) that was associated with Tourette syndrome (TS) and related conditions in a single family pedigree. Subsequent genetic work has provided further support for abnormalities of HA signaling in sporadic TS. As a result of this genetic work, Hdc knockout mice, which were generated more than 15 years ago, have been reexamined as a model of the pathophysiology of TS and related conditions. Parallel work in these KO mice and in human carriers of the Hdc mutation has revealed abnormalities in the basal ganglia system and its modulation by dopamine (DA) and has confirmed the etiologic, face, and predictive validity of the model. The Hdc-KO model thus serves as a unique platform to probe the pathophysiology of TS and related conditions, and to generate specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and recent and ongoing work using it to further investigate pathophysiological changes that may contribute to these disorders.

Keywords

  • Animal model
  • Histamine
  • Histidine decarboxylase
  • Obsessive–compulsive disorder
  • Tic disorders
  • Tourette syndrome

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Abbreviations

11C-GSK189254:

An H3 receptor PET tracer

11C-PBR28:

A PET tracer that binds to the peripheral benzodiazepine receptor, PBR, a marker of activated microglia

11C-PK11195:

A PET tracer that binds to activated microglia

ADHD:

Attention deficit-hyperactivity disorder

Akt:

Ak-thymoma protein kinase, also known as protein kinase B

ASD:

Autism spectrum disorder

AZD5213:

An H3R antagonist

C57Bl/6:

C57 Black-6 inbred mouse line

cAMP:

Cyclic adenosine monophosphate

CNV:

Copy number variation

D1R:

Dopamine D1 receptor

D2R:

Dopamine D2 receptor

DA:

Dopamine

DARPP-32:

Dopamine- and cAMP-regulated phosphoprotein

dMSN:

Direct/striatonigral pathway medium spiny neuron

GABA:

Gamma-aminobutyric acid

GPe:

Globus pallidus, pars externa

GPi:

Globus pallidus, pars interna

GSK3beta:

Glycogen synthase kinase 3-beta

GWAS:

Genome-wide association study

H1R:

Histamine H1 receptor

H2R:

Histamine H2 receptor

H3R:

Histamine H3 receptor

H4R:

Histamine H4 receptor

HA:

Histamine

Hdc:

Histidine decarboxylase gene

Hdc-KO:

Histidine decarboxylase knockout mouse

IGF-1:

Insulin-like growth factor 1

IL-1:

Interleukin 1

iMSN:

Indirect/striatopallidal pathway medium spiny neuron

JNJ5207852:

An H3R receptor antagonist

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

mRNA:

Messenger ribonucleic acid

MSN:

Medium spiny neuron

OCD:

Obsessive–compulsive disorder

PANDAS:

Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus

PET:

Positron emission tomography

PHNO:

(+)-4-Propyl-9-hydroxynaphthoxazine

PPI:

Prepulse inhibition

RAMH:

R-aminomethylhistamine, an H4R agonist

SMA:

Supplementary motor area

SNc:

Substantia nigra, pars compacta

SNr:

Substantia nigra, pars reticulata

STN:

Subthalamic nucleus

Th1:

Type-1 T-helper cell

TS:

Tourette syndrome

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Pittenger, C. (2017). Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions. In: Hattori, Y., Seifert, R. (eds) Histamine and Histamine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 241. Springer, Cham. https://doi.org/10.1007/164_2016_127

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