Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders

Background Interneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS. Methods To test the causal importance of these neuronal abnormalities, we have recapitulated them in vivo in developmentally normal mice, using a combination transgenic-viral strategy for targeted toxin-mediated ablation. Results We find that conjoint ~40% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice; since ASD and TS have a marked male predominance, this observation reinforces the potential relevance of this finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in males after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum; these alterations were not observed after disruption of only one interneuron type, or in doubly-depleted females. Conclusions These data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner.

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“…Locomotor activity was assessed using an open field apparatus (Omnitech Electronics) as described previously (37, 38). …”

Section: Methodsmentioning

confidence: 99%

“…Following behavioral testing, brains were removed, fixed, sliced, and immunostained as described previously (37, 38, 45, 46). …”

Section: Methodsmentioning

confidence: 99%

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

Rapanelli

Frick

et al. 2017

Biological Psychiatry

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“…In our laboratories, we have used a range of methods to quantify repetitive movements, including manual scoring from videos (Castellan Baldan et al, 2014; Pogorelov et al, 2015; Xu et al, 2015a; Xu et al, 2015b; Xu et al, 2016), automated scoring from videos (Rapanelli et al, in press; Xu et al, 2015a), and repetitive beam-breaks in an open field (Rapanelli et al, 2017; Rapanelli et al, in press). Standardization is needed; however, in light of the discussion above, standardized approaches to quantification of behavioral pathology need to be somewhat flexible – the precise topography of tic-relevant movements may not be identical across models and across contexts.…”

Section: Studying Tic-like Movements Using a Phenomenological Approachmentioning

confidence: 99%

“…Hdc -KO mice also show impaired PPI (as do TS patients carrying a mutated Hdc allele), providing further validation (Castellan Baldan et al, 2014). Parallel studies in these mice and in patients carrying the Hdc mutation have identified abnormalities in DA modulation of the striatum and in dopamine D2/D3 receptors in the substantia nigra as a potential locus of pathology and/or homeostatic regulation in tic disorders (Castellan Baldan et al, 2014; Rapanelli et al, 2017; Rapanelli et al, 2014). …”

Section: Modeling Tics Based On Specific Pathophysiological Hypothesesmentioning

confidence: 99%

Modeling tics in rodents: Conceptual challenges and paths forward

Bortolato

Pittenger

2017

Journal of Neuroscience Methods

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Background Recent advances in our understanding of the neurobiology of tics have led to the development of novel rodent models capturing different pathophysiological and phenotypic aspects of Tourette syndrome. The proliferation of these models, however, raises vexing questions on what standards should be adopted to assess their theoretical validity and empirical utility. Assessing the homology of a rodent motoric burst with a tic remains problematic, due to our incomplete knowledge of the underpinnings of tics, their high phenotypic complexity and variability, limitations in our ability test key aspects of tic phenomenology (such as premonitory sensory phenomena) in animals, and between-species differences in neuroanatomy and behavioral repertoire. These limitations underscore that any interpretation of behavioral output in an animal model cannot exclusively rely on the recognition of features that bear superficial resemblance with tics, but must be supported by other etiological and convergent phenomenological criteria. New method Here, we discuss two complementary approaches for the study and validation of tic-like manifestations in rodents, based respectively on the use of contextual modulators and accompanying features of repetitive motor manifestations and on the reproduction of pathogenic factors. Results Neither strategy can by itself provide convincing evidence that a model informatively recapitulates tic pathophysiology. Their combination holds promise to enhance the rigorous evaluation and translational relevance of rodent models of tic disorders. Conclusions This systematic consideration of different approaches to the validation and study of animal models of tic pathophysiology provides a framework for future work in this area.

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“…The H 3 R agonist immepip has not been found to affect intra-striatal DA levels in wild-type mice (Alfaro-Rodriguez et al, 2013). Similarly, systemic administration of the specific agonist R-aminomethylhistamine (RAMH), at doses that produce behavioral effects (see below; Rapanelli et al, in press), does not produce the predicted reduction in striatal DA – in fact, in KO mice it produces a small but significant elevation in DA after RAMH challenge (Rapanelli et al, in press; Rapanelli et al, 2016). The ability of both endogenous and exogenous HA to reduce striatal DA levels (Castellan Baldan et al, 2014) can be concluded to depend on different receptors.…”

Section: Introductionmentioning

confidence: 99%

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

Pittenger

2017

Handbook of Experimental Pharmacology

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While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relation 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 of specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and summarize recent and ongoing work using it to further investigate pathophysiological changes that may contribute to TS and related conditions.

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Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders

Cited by 43 publications

References 56 publications

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

Modeling tics in rodents: Conceptual challenges and paths forward

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

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