# Histamine Regulation of the Basal Ganglia and the Pathophysiology of Tics

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $411,200

## Abstract

ABSTRACT
Tourette syndrome (TS) and other tic disorders affect up to 5% of the population and are frequently comorbid
with other neuropsychiatric conditions. Their neurobiology is poorly understood, and current treatments are
often inefficacious. Recent genetic findings implicate dysregulation of histamine (HA) signaling as a rare
cause; in a recent paper in Neuron we established the HA-deficient histidine decarboxylase (Hdc) knockout
mouse as a model of tic pathophysiology that has etiologic, face, and predictive validity.
Convergent evidence implicates the cortico-basal ganglia circuitry in tic disorders. In particular, dysregulation
of dopamine (DA) in the striatum is thought to be an important contributing factor. HA receptors are highly
expressed in the basal ganglia circuitry. HA regulates DA levels in the striatum: HA infusion in a wild-type
mouse reduces striatal DA in vivo, and the HA-deficient Hdc-KO model has elevated basal DA levels. In our
first Aim we will elucidate the mechanisms of this poorly understood regulatory interaction. We hypothesize
that HA acts on H1R receptors found on inhibitory interneurons in the substantia nigra pars compacta (SNc).
We will test this using in vivo pharmacology and microdialysis. We will then test the necessity and sufficiency
of HA-induced SNc interneuronal activity for striatal DA regulation, using a novel chemogenetic strategy.
Baseline DA dysregulation and repetitive behavioral pathology in the Hdc-KO tic model are subtle, but they are
dramatically increased by behavioral or pharmacological perturbations. For example, stress induces repetitive
behaviors in the model. Local neuronal disinhibition in the striatum produces a dramatic spike in DA, not seen
in WT animals. This suggests a loss of DA homeostasis, rendering the system subject to phasic instability – a
pattern that resembles the phasic phenomenology of tic disorders. We hypothesize that loss of H1R tone on
SNc interneurons removes a source of homeostatic regulation; we will test this in our second Aim.
We find much more dramatic repetitive behavioral pathology after HA neurons are chemogenetically silenced
in vivo. This suggests that mitigating mechanisms constrain behavioral pathology in the KO animal.
Identification of such mechanisms is of both basic and translational importance; enhancing them may
represent a novel therapeutic strategy, both in tic disorders and in other hyperdopaminergic pathologies. We
will arbitrate between two possible explanations for this observation in Aim #3. First, behavioral pathology may
be more profound after acute silencing of HA neurons because it also disrupts GABA cotransmission, which is
intact in the KO animals. Second, KO animals may develop compensations over ontogeny. We will use a
combination of chemogenetics and shRNA knockdown to test these two hypotheses.
In the long term, this innovative research program is of both basic and translational importance, aiming to
elucidate the normal role of HA...

## Key facts

- **NIH application ID:** 9849336
- **Project number:** 5R01NS101104-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Christopher John Pittenger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,200
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849336

## Citation

> US National Institutes of Health, RePORTER application 9849336, Histamine Regulation of the Basal Ganglia and the Pathophysiology of Tics (5R01NS101104-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9849336. Licensed CC0.

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