Astrocytic and neuronal localization of kynurenine aminotransferase-2 in the adult mouse brain

Abstract

During catabolism of tryptophan through the kynurenine (KYN) pathway, several endogenous metabolites with neuromodulatory properties are produced, of which kynurenic acid (KYNA) is one of the highest significance. The causal role of altered KYNA production has been described in several neurodegenerative and neuropsychiatric disorders (e.g., Parkinson's disease, Huntington's disease, schizophrenia) and therefore kynurenergic manipulation with the aim of therapy has recently been proposed. Conventionally, KYNA is produced from its precursor L-KYN with the aid of the astrocytic kynurenine aminotransferase-2 (KAT-2) in the murine brain. Although the mouse is a standard therapeutic research organism, the presence of KAT-2 in mice has not been described in detail. This study demonstrates the presence of kat-2 mRNA and protein throughout the adult C57Bl6 mouse brain. In addition to the former expression data from the rat, we found prominent KAT-2 expression not only in the astrocyte, but also in neurons in several brain regions (e.g., hippocampus, substantia nigra, striatum, and prefrontal cortex). A significant number of the KAT-2 positive neurons were positive for GAD67; the presence of the KAT-2 enzyme we could also demonstrate in mice brain homogenate and in cells overexpressing recombinant mouse KAT-2 protein. This new finding attributes a new role to interneuron-derived KYNA in neuronal network operation. Furthermore, our results suggest that the thorough investigation of the spatio-temporal expression pattern of the relevant enzymes of the KYN pathway is a prerequisite for developing and understanding the pharmacological and transgenic murine models of kynurenergic manipulation.

Age‐ and disease‐specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease

“…Reduced cerebral KA production in PD and AD could also be the consequence of cell-specific changes in the brain. Astrocytes are considered the primary source of extracellular KA concentrations (Guillemin et al 2001;Kiss et al 2003) and studies in rodents showed that kynurenine aminotransferase II (KATII)the enzyme that converts Kyn to KAwas strongly localized to astrocytes (Guidetti et al 2007;Her edi et al 2017;Song et al 2018). In response to activated microglia, astrocytes can change their molecular behavior during diseases of the brain (Liddelow et al 2017).…”

Alterations of Astrocytes in the Context of Schizophrenic Dementia

“…In schizophrenia, there is hypofunction of NMDA receptors, which leads to a decrease in prefrontal cortex functions (Herédi et al, 2017). Weakened prefrontal cortex function associated with NMDA receptor hypofunction may be involved in the development of negative and cognitive symptoms.…”

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…It is produced by kynurenine aminotransferases (KATs) and can influence glutamatergic neurotransmission at several levels and have exerted neuroprotective effects in several paradigms [5,202,210,267,268]. KYNA is capable of exerting a wide-spectrum of endogenous antagonistic effects at ionotropic excitatory amino acid receptors [269].…”