Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8336151 | Journal of Chemical Neuroanatomy | 2018 | 52 Pages |
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 GLUâ¯+â¯DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLUâ¯+â¯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 â possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions.
Keywords
inhibitory G-proteinCSTCIEGMSNOCDPACAPISHN-methyl-d-aspartateNMDACaMKdorsomedialaCSFNpas2LIFmRNAI.U.neuronal PAS domain protein 2mPer1CREPBSCREB3′,5′-cyclic adenosine monophosphatecAMPCRE binding proteinobsessive-compulsive disorderCapillary electrophoresisanalysis of varianceANOVADopaminemessenger ribonucleic acidcholera toxincAMP response elementLaser-induced fluorescenceartificial cerebrospinal fluidPhosphate-buffered salinepituitary adenylate cyclase activating peptideImmediate-early genestimulatory G-proteinGABAgamma-amino butyric acidGluglutamate
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Authors
Kylie B. O'Brien, Anjail Z. Sharrief, Eric J. Nordstrom, Anthony J. Travanty, Mailee Huynh, Megan P. Romero, Katie C. Bittner, Michael T. Bowser, Frank H. Burton,