A transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder circuitry

Abstract

The tic disorder Tourette's Syndrome (TS) and obsessive-compulsive disorder (OCD) are comorbid behavioral disorders, suggesting a shared but still unknown neuronal basis. To 'circuit-test' such behaviors, we previously engineered transgenic mice expressing a neuropotentiating protein (cholera toxin A1 subunit) within a cortical-limbic subset of dopamine D1-receptor expressing (D1+) neurons known to trigger glutamatergic excitation of orbitofrontal, sensorimotor, limbic and efferent striatal circuits thought to be hyperactive or affected in OCD and TS. These mice exhibited OCD-like behaviors including generalized behavioral perseveration and compulsion-like leaping and grooming-associated pulling and biting of skin and hair. We now report that these OCD-like mice, like humans, also exhibit comorbid TS-like behaviors, including juvenile-onset tics; increased tic number, complexity and flurries; increased tic severity in males; voluntary tic suppression; and tic responsiveness to a non-cataleptic TS+OCD drug therapy (clonidine, 0.01 mg kg −1 ). These data suggest that hormonal gender differences, apart from the influence of genetic or autoimmune etiologic factors, may be sufficient to aggravate tic severity in human TS males compared to TS females. These data also proffer a precise neuronal basis for TS+OCD, wherein tics and primary compulsions or obsessions are evoked by hyperactivity of various cortical-limbic projection neurons' glutamatergic output to efferent targets like the striatum. The 'Cortical-limbic Glutamatergic Neuron' (CGN) neuronal circuit model merges formerly opposed neurotransmitter models of TS and OCD, and is consistent with new clinical reports of increased cortical hyperactivity, striatal glutamate and striatal inhibitory D2 receptors, and reduced striatal responsiveness, in these disorders.

Tourette's syndrome and associated disorders: a systematic review

“…In an experimental study, Nordstrom et al 25 found that the hypoactivity of glutamatergic efferent cortical-limbic pathways leads to ADHD.…”

“…25,34 Some hormones seem to play a role in the cooccurrence of TS+OCD. The onset and recurrence of TS have been associated with significant emotional contexts.…”

Obsessive-compulsive disorder phenotypes: implications for genetic studies

“…15 The majority of studies conducted to date have focused on genes important in the serotonin and dopaminergic neurotransmitter systems due to the efficacy of serotonin reuptake inhibitors (SRIs) and dopamine antagonists in the treatment of OCD patients. [16][17][18] In summary, even though the genetic transmission of OCD is indisputable, the mode of transmission and the genes involved are still unknown. A major difficulty in genetic studies of complex disorders such as OCD has been sample heterogeneity.…”

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder

“…This is presumed to increase their firing rate in a way that may resemble the hyperactive limbic cortical areas seen in functional imaging of OCD patients; indeed, these transgenic mice are described as engaging in perseverative behaviors that mimic some aspects of OCD and Tourette's syndrome. 78,79 MK-801, a noncompetitive use-dependent antagonist of the NMDA glutamate receptor that may indirectly increase presynaptic glutamate release, 80 has been shown to worsen these perseverative behaviors, and to induce an additional category of "limbic seizure-like" stereotypies. 81 Interestingly, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of AMPA-type glutamate receptors, does not affect baseline OCD-like behaviors in these mice or their exacerbation by MK-801, but does reduce the "seizure-like" stereotypies.…”