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

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.

Figure 1. Major pathways through the cortico-basal ganglia circuitry

Dysregulation of the cortico-basal ganglia circuitry is implicated in TS and tic disorders, as well as in OCD and related conditions (Leckman et al, 2010; Maia et al, 2008; Pittenger, 2017). Projections from the cortex and thalamus through the nuclei of the basal ganglia can be conceptualized as traversing two pathways: the direct pathway, which polysynaptically disinhibits thalamic feedback to cortex, and the indirect pathway, which polysynaptically inhibits this feedback. Balance between these two pathways is regulated by dopamine and, perhaps, by histamine. In the Hdc-KO model of TS pathophysiology (and, it is proposed, in TS and tic disorders in humans), both DA dysregulation and HA deficiency lead to hyperactivity in the direct pathway and hypoactivity in the indirect pathway; the latter, in particular, may lead to deficient inhibition of off-target action patterns, which may manifest as tics and other repetitive behaviors. See text for further details. Adaptd from Pittenger, Bloch, and Williams, 2011.

Figure 2. Stereotypies in Hdc KO mice

A. Stereotypies after D-amphetamine (8.5 mg/kg) were potentiated in Hdc KO and Het mice; pretreatment with haloperidol mitigated this effect. From Castellan Baldan et al, 2014, with permission. B. Stress, induced by tone fear conditioning, similarly increased stereotypical grooming. Adapted from Xu et al, 2015b. C. Prepulse inhibition (PPI), a measure of sensorimotor gating, was reduced in human carriers of the Hdc W317X mutation. D. PPI is similarly reduced in Hdc heterozygotes and knockouts. Data are shown for a 6 dB prepulse; similar effects were seen with larger prepulses. C and D from Castellan Baldan et al, 2014, with permission.

Figure 3. D2/D3 receptors in humans and mice with a mutated Hdc gene

A–D. D2/D3R receptor availability in TS patients carrying the Hdc-W317X mutation, relative to matched controls, measured using in vivo ¹¹C-PHNO PET imaging. A,B composite radioligand binding images from patients (middle row) and controls (bottom row). C. Binding in subnuclei of the basal ganglia. D. Individual subject binding in the substantia nigra in patients and controls; group means are show by a horizontal line. E-G. D2/D3R receptor binding in mice measured ex vivo using ³H-raclopride binding. E Raclopride binding in the substantia nigra. F. Increased binding was seen in Hdc het and KO mice; individual data are shown. G. Reduced raclopride binding was seen in dorsal striatum; this correlated negatively, on an animal-by-animal basis, with the increased binding in the nigra. From Castellan Baldan et al, 2014, with permission.