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Astrocytes Regulate Cortical Ach Release Via Kynurenic Acid: Implications For Cognitive Impairments In Schizophrenia

Zmarowski, Amy L.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1217199677

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Psychology.
The basal forebrain cholinergic system (BFCS) innervating the prefrontal cortex (PFC) is essential for attention and cognition; aberrations in this system underlie various symptoms in schizophrenia. Dopamine (DA) and glutamate (Glu) modulate cortical acetylcholine (ACh) release within the PFC and distributed regions like the nucleus accumbens (NAC). The NAC links discriminative cues and salient stimuli to bias BFCS activity under heightened motivation through modulation of cortical ACh by NAC DA and Glu. Dysfunctional interactions between the neurotransmitters of this NAC-BF-PFC circuit are implicated in the pathophysiology of schizophrenia. Astrocytes produce the gliotransmitter kynurenic acid (KYNA) that modulates neurotransmission. KYNA antagonizes α7 nicotinic ACh receptors at physiological concentrations and modest changes in KYNA inversely regulate DA and Glu release. KYNA is elevated in schizophrenia and normalized with chronic neuroleptic treatment, thus implicating imbalances in KYNA in the disorder. This thesis determined a role for KYNA in regulating cortical ACh release and in PFC-mediated tests of cognitive flexibility that are characteristically impaired in schizophrenia. The first two experiments used microdialysis to determine ACh is tonically inhibited by KYNA in the PFC and the NAC. The final experiments determined whether elevating KYNA impaired cognitive flexibility (switching response strategies between various stimuli) depending on changing task rules. We used an animal set-shifting task requiring discrimination between two stimuli (brightness and texture) for a reward. Rats were trained to discriminate between stimuli (color-black) on day 1 until reaching a criterion performance level. On day 2 animals were trained on the alternative extra-dimensional (ED) strategy (texture-smooth). Elevating KYNA by administrating kynurenine (50 mg/kg, i.p.) did not impair initial rule acquisition, but impaired ED shifting for animals treated prior to Set 2 (28% reached criterion) relative to saline-treated controls (83% reached criterion). Intra-PFC infusion of kynurenine paralleled the systemic data; treatment prior to Set 2 significantly impaired ED shifting (16% reached criterion) without impacting initial rule learning. Collectively these data suggest elevated KYNA may contribute to neurotransmitter dysfunctions and cognitive deficits in schizophrenia symptomotologies and suggest normalizing KYNA may provide novel and more efficacious pharmacotherapies for the disorder.
John Bruno, PhD (Advisor)
Lane Wallace, PhD (Committee Member)
Gary Wenk, PhD (Other)
Ben Givens, PhD (Other)
138 p.
Psychobiology
KYNA; cognitive flexibility; schizophrenia; ACh; glutamate; PFC

Recommended Citations

Citations

  • Zmarowski, A. L. (2008). Astrocytes Regulate Cortical Ach Release Via Kynurenic Acid: Implications For Cognitive Impairments In Schizophrenia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1217199677

    APA Style (7th edition)

  • Zmarowski, Amy. Astrocytes Regulate Cortical Ach Release Via Kynurenic Acid: Implications For Cognitive Impairments In Schizophrenia. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1217199677.

    MLA Style (8th edition)

  • Zmarowski, Amy. "Astrocytes Regulate Cortical Ach Release Via Kynurenic Acid: Implications For Cognitive Impairments In Schizophrenia." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1217199677

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.