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

Cell Rep. 2016 Oct 4;17(2):570-582. doi: 10.1016/j.celrep.2016.09.029.


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.

Keywords: 22Q11.2; GAD; L-proline; PRODH; gamma oscillations; in vivo neural circuits; neuroactive metabolites; psychiatric diseases; schizophrenia; synaptic plasticity.

MeSH terms

  • Animals
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Cytosol / metabolism
  • Disease Models, Animal
  • Gamma Rhythm
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / antagonists & inhibitors
  • Humans
  • Mice
  • Proline / deficiency*
  • Proline / genetics
  • Proline Oxidase / deficiency
  • Proline Oxidase / genetics*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Schizophrenia / pathology
  • Vigabatrin / administration & dosage
  • gamma-Aminobutyric Acid / metabolism*


  • gamma-Aminobutyric Acid
  • Proline
  • Proline Oxidase
  • Glutamate Decarboxylase
  • Vigabatrin