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 in the basal ganglia, establish how its perturbation can lead to tics, and identify potential new treatment targets.
The pathophysiology of tic disorders is not well understood, but recent advances implicating abnormalities in the brain's histamine (HA) modulatory system have led to the development of a new model of tic pathophysiology, the histidine decarboxylase (Hdc) knockout mouse, that has great potential to shed light on the mechanisms underlying tics and the identification of new potential treatment targets. In this proposal we seek to better understand how HA regulates the basal ganglia circuitry, which are implicated in tic disorders, and how disruption of this regulation leads to pathology. In particular, we hypothesize that HA deficiency disinhibits dopamine (DA) release and renders the system more susceptible to exogenous perturbation, but that other mechanisms, which we will probe, constrain the development of DA dysregulation and behavioral pathology - mechanisms that may represent promising therapeutic targets.
|Rapanelli, Maximiliano; Frick, Luciana; Jindachomthong, Kantiya et al. (2018) Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology. Neuroscience 392:172-179|
|Rapanelli, Maximiliano; Frick, Luciana; Bito, Haruhiko et al. (2017) Histamine modulation of the basal ganglia circuitry in the development of pathological grooming. Proc Natl Acad Sci U S A 114:6599-6604|