Schizophrenia (SZ) is a neurodevelopmental disorder in which the interaction of genetic and environmental factors results in chronic, debilitating impairments in several core symptom clusters. Of these, cognitive control deficits - indicated by executive functions such as attention and working memory - represent a primary indicator of functional outcome for these patients that remain poorly treated by current pharmacotherapies. Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan degradation that acts as an alpha 7 nicotinic acetylcholine receptor antagonist at physiological concentrations. KYNA is increased in the cerebrospinal fluid and postmortem brain tissues of SZ patients and given its antagonistic properties at presynaptic alpha 7 nAChRs may therefore represent a pathological mechanism that contributes to dysregulated neurotransmission and observed cognitive impairments in this patient population. KYNA has been demonstrated to modulate acetylcholine and glutamate, two neurotransmitters that are integral to prefrontally mediated executive functions that are impaired in SZ patients. The association between increased KYNA and cognitive dysfunction is therefore of great clinical relevance and there are several current animal models of SZ that focus on cognitive impairments following KYNA elevations. One model, which will be discussed in this thesis, is the acute model whereby KYNA is elevated in the brain by systemic administration of its bioprecursor, L kynurenine (KYN), which readily crosses the blood-brain barrier and is converted to KYNA within astrocytes.
We have previously established that KYNA bidirectionally modulates prefrontal glutamate and acetylcholine in the PFC and that KYN (100 mg/kg) results in cognitive inflexibility in the prefrontally mediated attentional set-shifting task. The present thesis further examined the hypothesis that astrocyte-derived KYNA levels impair prefrontally mediated cognitive flexibility tasks through reductions of cortical glutamatergic and/or cholinergic transmission via alpha 7 nAChR modulation. The first experiment assessed dose-response relationships and revealed that acute KYN administration (6.25, 25, 100 mg/kg) results in extradimensional set shifting deficits relative to saline controls, with no increase in severity of deficit with increasing dose (e.g., a flat dose response). In contrast, first reversal deficits were noted at doses of 25 and 100 mg/kg suggesting a dissociation of stage effect at a dose level of 6.25. Set shifting deficits induced by KYN (100 mg/kg) were reversed by pretreatment with the alpha 7 nAChR partial agonist SSR180711 (3 mg/kg), indicating that the effects of KYN on set shifting performance are due to action of increased KYNA on alpha 7 nAChRs. Collectively, these experiments further validate the use of KYN to model cognitive dysfunction in SZ and support the use of alpha 7 nAChR modulators to enhance cognition.