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.
Highlights
There are a large number of relatively rare human diseases in which genetic mutations result in dysfunction of distinct enzymes embedded within metabolic networks, leading in turn to the pathological accumulation of specific metabolites
Isolated Deficits in Sustained GABA Release in Mice with Elevated CNS L-Proline To look for possible alterations in evoked synaptic transmission caused by L-proline accumulation within the CNS, we performed patch-clamp recordings from layer II/III pyramidal neurons of the medial prefrontal cortex in acute brain slices prepared from 4- to 6-week-old hyperprolinemic ProdhÀ/À mice and wild-type (WT) littermates (Gogos et al, 1999)
We chose to examine evoked synaptic transmission at layer II/III pyramidal neurons as action potential-mediated neurotransmission between neurons within this layer is believed to be critically involved in local network computations in the PFC, a brain region that has been strongly implicated in the pathophysiology of schizophrenia and psychosis (Uhlhaas and Singer, 2010; Bartos et al, 2007)
Summary
There are a large number of relatively rare human diseases in which genetic mutations result in dysfunction of distinct enzymes embedded within metabolic networks, leading in turn to the pathological accumulation of specific metabolites. A substantial body of clinical data supports that elevated CNS L-proline may cause neuronal dysfunction by interfering with native neurotransmitter systems (Willis et al, 2008) In this regard, we noted the chemical structure of L-proline closely resembles that of GABA, suggesting pathological levels of L-proline might disrupt normal GABA-ergic function. Our results highlight a unique mechanism of neuronal dysfunction in psychiatric disorders whereby cytosolic accumulation of a neuroactive metabolite disrupts neurotransmitter synthesis leading to a specific synaptic dysfunction This finding raises the possibility of a potentially broader, important contribution of both GABA-mimetic and other neuroactive metabolites in accounting in part for the large genetic and neural heterogeneity of neuropsychiatric disease (Rodriguez-Murillo et al, 2012)
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