The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling

Hippocampal hyperactivity in schizophrenia is an early abnormality linked to its pathognomonic symptoms. An upregulation of the ‘glutamate metabolic cycle’, a pathway dedicated to maintaining normal synaptic excitability, is hypothesized to be pathogenic and to have therapeutic potential. Testing the hypothesis requires profiling the pathway’s three key metabolites -- glutamate, glutamine, and GABA. We begin by using a newly developed processing method capable of measuring these hippocampal metabolites via standard 1H-magnetic resonance spectroscopy (1H-MRS). We profiled the metabolites in patients with attenuated psychotic symptoms, a cohort enriched for early-stage schizophrenia and related psychotic disorders. More than just confirming abnormal pathway upregulation, the resultant profile isolated glutaminase 1 (GLS1) as the pathogenic driver. GLS1-dependent pathway upregulation was found to mechanistically underlie hippocampal hyperactivity and to associate with the illness’ symptoms. Next, to test the pathway’s therapeutic potential we used a newly developed 1H-MRS acquisition protocol optimized to measure the metabolites in mice. Hippocampal profiling GLS1 haploinsufficient mice showed that the pathway can be safely downregulated and identified a therapeutic goal. Profiling the effects of a GLS1 inhibiter that belongs to a drug family approved for clinical trials shows that the pathway can be pharmacologically targeted. Finally, profiling the effect of the inhibitor using the benchmark, ex-vivo mass spectrometry, validates that the new 1H-MRS tools are reliable biomarkers. Collectively, our findings can accelerate drug development for an illness that first strikes the hippocampus of young people before pathologically progressing and resulting in lifelong morbidity.