Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-prolin...

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Veröffentlicht in:Cell reports (Cambridge) 2016-10, Vol.17 (2), p.570-582
Hauptverfasser: Crabtree, Gregg W., Park, Alan J., Gordon, Joshua A., Gogos, Joseph A.
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Sprache:eng
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Zusammenfassung:Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease. [Display omitted] •Elevated L-proline leads to deficits in sustained GABA release and gamma oscillations•Structural homology of L-proline and GABA suggests L-proline is a GABA-mimetic•Disease-relevant L-proline levels impair GABA production due to GAD blockade•Elevation of cytosolic GABA with vigabatrin rescues synaptic deficits L-proline accumulates in human disease, but how it causes neural dysfunction is unknown. Here, Crabtree et al. provide evidence that L-proline is a GABA-mimetic and find that disease-relevant concentrations impair GABA production leading to deficits in sustained GABA-ergic transmission and gamma oscillations.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2016.09.029