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 |
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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.
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•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. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2016.09.029 |