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

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

doi:10.1016/j.jchemneu.2018.02.007

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

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

Chemistry (Twin Cities)

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	11-20
Number of pages	10
Journal	Journal of Chemical Neuroanatomy
Volume	89
DOIs	https://doi.org/10.1016/j.jchemneu.2018.02.007
State	Published - Apr 2018

Bibliographical note

Funding Information:
The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression , the National Alliance for the Mentally Ill , and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB].

Funding Information:
The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression, the National Alliance for the Mentally Ill, and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB].

Publisher Copyright:
© 2018 The Authors

Keywords

Compulsion
D-serine
Glutamate
Per1
Tourette
Transgenic

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title = "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.",

keywords = "Compulsion, D-serine, Glutamate, Per1, Tourette, Transgenic",

author = "O'Brien, {Kylie B.} and Sharrief, {Anjail Z.} and Nordstrom, {Eric J.} and Travanty, {Anthony J.} and Mailee Huynh and Romero, {Megan P.} and Bittner, {Katie C.} and Bowser, {Michael T.} and Burton, {Frank H.}",

note = "Funding Information: The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression , the National Alliance for the Mentally Ill , and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB]. Funding Information: The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression, the National Alliance for the Mentally Ill, and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB]. Publisher Copyright: {\textcopyright} 2018 The Authors",

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doi = "10.1016/j.jchemneu.2018.02.007",

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T1 - Biochemical markers of striatal desensitization in cortical-limbic hyperglutamatergic TS- & OCD-like transgenic mice

AU - O'Brien, Kylie B.

AU - Sharrief, Anjail Z.

AU - Nordstrom, Eric J.

AU - Travanty, Anthony J.

AU - Huynh, Mailee

AU - Romero, Megan P.

AU - Bittner, Katie C.

AU - Bowser, Michael T.

AU - Burton, Frank H.

N1 - Funding Information: The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression , the National Alliance for the Mentally Ill , and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB]. Funding Information: The authors thank Dr. Mary E. Harrington (Smith College) for helpful advisory supervision and training assistance to AZS. This work was supported by the National Institutes of Health [grant numbers NS043304 to MTB, R03MH53553 to FHB, R21NS045566 to FHB]; the National Alliance for Research on Schizophrenia and Depression, the National Alliance for the Mentally Ill, and the Rochester Area Alliance for the Mentally Ill [Jeff Sutton Memorial NARSAD-NAMI-RAAMI Young Investigator Award to FHB]; and research grants from the Tourette Syndrome Association [FHB] and the University of Minnesota Foundation [Orphan Therapeutic Fund to FHB]. Publisher Copyright: © 2018 The Authors

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

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KW - D-serine

KW - Glutamate

KW - Per1

KW - Tourette

KW - Transgenic

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

Abstract

Bibliographical note

Keywords

UN SDGs

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