Role of Endogenous Metabolite Alterations in Neuropsychiatric Disease

The potential role in neuropsychiatric disease risk arising from alterations and derangements of endogenous small-molecule metabolites remains understudied. Alterations of endogenous metabolite concentrations can arise in multiple ways. Marked derangements of single endogenous small-molecule metabolites are found in a large group of rare genetic human diseases termed "inborn errors of metabolism", many of which are associated with prominent neuropsychiatric symptomology. Whether such metabolites act neuroactively to directly lead to distinct neural dysfunction has been frequently hypothesized but rarely demonstrated unequivocally. Here we discuss this disease concept in the context of our recent findings demonstrating that neural dysfunction arising from accumulation of the schizophrenia-associated metabolite l-proline is due to its structural mimicry of the neurotransmitter GABA that leads to alterations in GABA-ergic short-term synaptic plasticity. For cases in which a similar direct action upon neurotransmitter binding sites is suspected, we lay out a systematic approach that can be extended to assessing the potential disruptive action of such candidate disease metabolites. To address the potentially important and broader role in neuropsychiatric disease, we also consider whether the more subtle yet more ubiquitous variations in endogenous metabolites arising from natural allelic variation may likewise contribute to disease risk but in a more complex and nuanced manner.