Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the α7nACh Negative Modulator Kynurenic Acid

Abstract

Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of ␣7-nicotinic acetylcholine receptors (␣7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an ␣7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABA A R positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

“…By contrast, during inflammation, KA may function as an NMDA receptor antagonist and, therefore, KA may have neuroprotective properties [70,71]. Surprisingly, endogenous KA has been shown to activate dopaminergic neurons in the rat ventral tegmental area through glutamatergic mechanisms [72].…”

Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia

“…This activation is thought to be induced indirectly by inhibition of afferent GABAergic projections from the prefrontal cortex and/or subcortical areas (Carr and Sesack, 2000; Kalivas et al, 1993; Patton et al, 2013; Phillipson, 1979; Sesack et al, 1989), or by local interneurons within the VTA (Tan et al, 2012; van Zessen et al, 2012; see Erhardt and Engberg, 2002; Erhardt et al, 2002). Of note in this context, submicromolar concentrations of KYNA antagonize α*7-nicotinic receptor function in the prefrontal cortex, resulting in the inhibition of GABAergic neurons (Flores-Barrera et al, 2017). Although the effect of KYNA on the α*7-nicotinergic receptor does not seem to contribute to the regulation of VTA DA firing (Linderholm et al, 2016), this action appears important for terminal control of DA release, where acute local administration of nanomolar concentrations of KYNA reduces DA in the rat striatum (Rassoulpour et al, 2005).…”

Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task

“…Upon release, nanomolar concentrations of KYNA negatively modulate α7nAChR function in vivo (Alexander et al 2013;Pocivavsek etal. 2012), though the underlying mechanism(s) may be indirect and remain to be clarified (Albuquerque and Schwarcz 2013;Flores-Barrera et al 2017;Hilmas et al 2001;Lopes et al 2007;Stone 2019). In turn, antagonism of presynaptic α7nAChRs decreases the release and tone of several major neurotransmitters, including ACh (Zmarowski et al 2009), glutamate (Beggiato et al 2013;Konradsson-Geuken et al 2010;Potter et al 2010;Wu et al 2010), GABA (Beggiato et al 2014), and dopamine (Livingstone et al 2010).…”