Abstract
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i.e., radial glia cells (RGCs), enriched from human cerebral cortex at mid-gestation (16–19 gestational weeks). KYNA treatment significantly decreased RGCs proliferation and survival by antagonizing NMDAR. This alteration resulted in a reduced number of cortical progenitors and neurons while number and activation of astrocytes increased. KYNA treatment reduced differentiation of RGCs into GABAergic neurons, while differentiation into glutamatergic neurons was relatively spared. Furthermore, in mixed cortical cultures KYNA triggered an inflammatory response as evidenced by increased levels of the pro-inflammatory cytokine IL-6. In conclusion, elevated levels of KYNA play a significant role in human RGC fate determination by antagonizing NMDARs and by activating an inflammatory response. The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia.
Highlights
Kynurenic acid (KYNA) is an intermediate metabolite of the kynurenine pathway and the only naturally occurring antagonist of the glutamatergic NMDA receptor (NMDAR) in the human brain (Stone, 2013)
Using the enriched dorsal radial glia cells (RGCs) cultures, we explored whether isolated RGCs express NMDARs, the obligatory subunit NR1, since KYNA has a specific affinity toward the glycine site of the NR1 subunit (Zhuravlev et al, 2007)
We demonstrated that RGCs labeled with brain lipid binding protein (BLBP)+, intermediate progenitors labeled with Tbr2+, and a subpopulation of interneuron progenitors labeled with Nkx2.1+, all express the NR1 subunit
Summary
Kynurenic acid (KYNA) is an intermediate metabolite of the kynurenine pathway and the only naturally occurring antagonist of the glutamatergic NMDA receptor (NMDAR) in the human brain (Stone, 2013). Elevated levels of KYNA have been found in the cerebrospinal fluid and in post-mortem brains of adult schizophrenia (Sch) patients (Erhardt et al, 2001; Schwarcz et al, 2001; Sathyasaikumar et al, 2011; Holtze et al, 2012). Both stress and infections, in rats activates indoleamine 2,3 dioxygenase (IDO), a cytokine responsive enzyme that catalyzes the formation of kynurenine, which may impair brain development (Pocivavsek et al, 2014; Notarangelo and Pocivavsek, 2016). Exposure of the fetal brain to KYNA may establish a positive feed-back loop, whereby KYNA levels are further enhanced (Guillemin et al, 2001; Meyer et al, 2011; Schwieler et al, 2015)
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