Preferential Disruption of prefrontal GABAergic function by nanomolar concentrations of the α7nACh negative modulator kynurenic acid

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 pre-clinical 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 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. Data show that prefrontal infusions of KYNA selectively attenuated the inhibitory component of PFC local field potential responses, a disruption that resulted from local blockade of α7nAChR. At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through a α7nAChR-dependent presynaptic mechanism. As a result, the E-I 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-AR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of local field potential 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 as proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions. SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. Yet, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the E-I balance of prefrontal synaptic activity towards a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of α7nAChR signaling. Thus, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA.