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

Abstract

SUMMARY 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.

Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

“…A persistent glutamatergic dysfunction can induce a secondary dysregulation of frontal dopaminergic transmission (Balla, Sershen, Serra, Koneru, & Javitt, 2003), as well as a performance decline (Latysheva & Rayevsky, 2003;O'Donnell, Stemmelin, Nitta, Brouillette, & Quirion, 2003). Besides, proline has many different roles, suggesting it may function as an inhibitory, GABA-mimetic neurotransmitter (Crabtree, Park, Gordon, & Gogos 2016). Given this likely role of proline, a PRODH decrease may cause an increase in proline levels and a decrease of glutamate, resulting in a slower cerebral transmission and in an indirect dopamine increase.…”

Mitochondria in complex psychiatric disorders: Lessons from mouse models of 22q11.2 deletion syndrome

“…Extracellular proline at physiological concentrations can potentiate hippocampal NMDA (N‐methyl‐D‐aspartate) glutamate receptors . A recent report suggests that proline is a GABA mimetic that competes with intracellular GABA synthesis . The metabolic relations among proline, glutamate, and GABA; the possibility of proline acting as a neurotransmitter; the high incidence of hyperprolinemia in patients with 22q11DS; and evidence of sensorimotor‐gating deficits in Prodh ‐deficient mice all point to the importance of this mitochondrial enzyme in some aspects of 22q11DS pathophysiology .…”

“…Extracellular proline at physiological concentrations can potentiate hippocampal NMDA (N-methyl-D-aspartate) glutamate receptors [94]. A recent report suggests that proline is a GABA mimetic that competes with intracellular GABA synthesis [95]. The metabolic relations 1: Prodh encodes mitochondrial proline dehydrogenase, which is involved in proline metabolism and is interconnected to glutamate synthesis.…”

Structure, function, and mechanism of proline utilization A (PutA)

“…Deficiencies in PRODH are associated with schizophrenia and related neurological disorders [1, 5–7]. In this regard, elevated proline levels in Prodh −/− mice were found to inhibit glutamate decarboxylase, resulting in lower production of γ-aminobutyric acid (GABA) and lower GABA-ergic transmissions [8]. PRODH also has an important role in the metabolic changes associated with cancer [9–12].…”