title: Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.
abstract: 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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: gwc2@columbia.edu.
authors.forename: Gregg W
authors.initials: GW
authors.lastname: Crabtree
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY 10032, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Park
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Gordon
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Department of Neuroscience, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: jag90@cumc.columbia.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D065818:Gamma Rhythm; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D011392:Proline / Q000172:deficiency* / Q000235:genetics; D011394:Proline Oxidase / Q000172:deficiency / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020888:Vigabatrin / Q000008:administration & dosage; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D011392:Proline; D011394:Proline Oxidase; D005968:Glutamate Decarboxylase; D020888:Vigabatrin
keywords: 22Q11.2; GAD; L-proline; PRODH; gamma oscillations; in vivo neural circuits; neuroactive metabolites; psychiatric diseases; schizophrenia; synaptic plasticity