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

J Chem Neuroanat. 2018 Apr:89:11-20. doi: 10.1016/j.jchemneu.2018.02.007. Epub 2018 Feb 24.

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.

Keywords: Compulsion; Glutamate; Per1; Tourette; Transgenic; d-serine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / analysis*
  • Brain / metabolism
  • Brain / physiopathology*
  • Disease Models, Animal
  • Glutamine / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Obsessive-Compulsive Disorder / metabolism
  • Obsessive-Compulsive Disorder / physiopathology*
  • Tourette Syndrome / metabolism
  • Tourette Syndrome / physiopathology*

Substances

  • Biomarkers
  • Glutamine