Biochemical markers of striatal desensitization in cortical-limbic hyperglutamatergic TS- & OCD-like transgenic mice

Abstract

Tics and compulsions in comorbid Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) are associated with chronic hyperactivity of parallel cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Comorbid TS- & OCD-like behaviors have likewise been observed in D1CT-7 mice, in which an artificial neuropotentiating transgene encoding the cAMP-elevating intracellular subunit of cholera toxin (CT) is chronically expressed selectively in somatosensory cortical & amygdalar dopamine (DA) D1 receptor-expressing neurons that activate cortico/amygdalo-striatal glutamate (GLU) output. We've now examined in D1CT-7 mice whether the chronic GLU output from their potentiated cortical/limbic CSTC subcircuit afferents associated with TS- & OCD-like behaviors elicits desensitizing neurochemical changes in the striatum (STR). Microdialysis-capillary electrophoresis and in situ hybridization reveal that the mice's chronic GLU-excited STR exhibits pharmacodynamic changes in three independently GLU-regulated measures of output neuron activation, co-excitation, and desensitization, signifying hyperactive striatal CSTC output and compensatory striatal glial and neuronal desensitization: 1) Striatal GABA, an output neurotransmitter induced by afferent GLU, is increased. 2) Striatal d-serine, a glial excitatory co-transmitter inhibited by afferent GLU, is decreased. 3) Striatal Period1 (Per1), which plays a non-circadian role in the STR as a GLU + DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLU + DA- triggered ultradian urges and motions, is transcriptionally abolished. These data imply that chronic cortical/limbic GLU excitation of the STR desensitizes its co-excitatory d-serine & DA inputs while freezing its GABA output in an active state to mediate chronic tics and compulsions - possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions.

Biomarkers and Tourette syndrome: a systematic review and meta-analysis

“…Mahone et al ( 91 ) conducted a study that indicated an increase in Glu and GABA levels within the CSTC loop, leading to improved selective motor inhibition in children with TS. Additionally, the study conducted on D1CT-7 mice revealed a direct association between Glu release in the CSTC loop and tic disorder behavior ( 136 ). However, elevated levels of serum Glu and Asp have also been found in children with ADHD ( 137 ).…”

The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap

“…In one of these lines in which transgene expression was restricted to the piriform cortex, somatosensory cortex, and intercalated nuclei of the amygdala, the mice displayed a number of compulsivelike characteristics, including perseveration and repetition of normal behavior patterns and repetitive leaping (Campbell et al, 1999). Further work with this model showed that chronic cholera toxin activation of these D1 receptor-expressing neurons provoked glutamatergic overexcitation of striatal output neurons of the "direct" corticostriatal-thalamocortical pathway (McGrath et al, 2000;Nordstrom et al, 2015;O'Brien et al, 2018). In other animal models, compulsive lever-pressing in the SA model was reduced by a D1 antagonist (Joel and Doljansky, 2003), whereas repetitive species-typical behavioral patterns such as grooming in the rat (Taylor et al, 2010) and nest building in the rabbit (Hoffman and Rueda Morales, 2012) were respectively strengthened by a D1 agonist and reduced by a D1 antagonist.…”

Jing-an oral liquid alleviates Tourette syndrome via the NMDAR/MAPK/CREB pathway in vivo and in vitro

“…Additionally, it has been shown that Glu release in the CSTC loop is directly associated with tic disorder behaviour in D1CT-7 mice (TS transgenic model) (O'Brien et al. 2018 ).…”