Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Abstract

Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

“…Thus, experimental studies demonstrate that elevated KYNA affects brain glutamatergic/dopaminergic neurotransmission, hereby im plicating activation of the KYN pathway in established mod els of schizophrenia. 18,43,44 Moreover, elevated KYNA induces schizophrenia like behaviour, such as disrupted prepulse in hibition 45 and auditory sensory gating 46 as well as impaired contextual discriminations, 47 spatial working memory 48,49 and attentional set shifting, 50 in rodents. Notably, a specific inhib itor of KYN aminotransferase II, which reduces brain KYNA levels, prevents ketamine induced working memory impair ments and tends to attenuate hallucinatory like behaviours in primates.…”

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

“…Moreover, KYNA levels are significantly elevated in the brain and the cerebrospinal fluid of individuals with schizophrenia, and in the brain of Alzheimer's disease patients, raising the possibility that enhanced inhibition of a7nAChRs and NMDARs by KYNA has a causative role in the defining cognitive deficits seen in these diseases (Baran et al, 1999;Erhardt et al, 2001;Schwarcz et al, 2001). Indeed, acute systemic administration of kynurenine or peripheral KMO inhibition not only leads to increases in brain KYNA (Carpenedo et al, 1994;Russi et al, 1992;Swartz et al, 1990) but also causes distinct cognitive impairments in experimental animals (Chess and Bucci, 2006;Chess et al, 2007;Erhardt et al, 2004;Shepard et al, 2003). By contrast, we showed recently that chronic reduction of brain KYNA in KAT-II-knockout mice improves cognitive performance (Potter et al, 2010).…”

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

“…However, ketamine has shown to impair gating of responses to repeated clicks presented at 100 ms intervals (Boeijinga et al, 2007) and reduce AEP response to the first click in rodents (Amann et al, 2009). The endogenous NMDA antagonist kynurenic acid also disrupts AEP N40 sensory gating (Shepard et al, 2003).…”