A transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder circuitry.
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.
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455-0217, USA.
E J
EJ
Nordstrom
F H
FH
Burton
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002772:Cholera Toxin / Q000235:genetics*; D003000:Clonidine / Q000494:pharmacology; D015897:Comorbidity; D005260:Female; D015994:Incidence; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009771:Obsessive-Compulsive Disorder / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D012727:Sex Characteristics; D020323:Tics / Q000503:physiopathology; D005879:Tourette Syndrome / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*
D000700:Analgesics; D017447:Receptors, Dopamine D1; D002772:Cholera Toxin; D003000:Clonidine