The glutamate system is complex; it includes multiple modulating cotransmitters, interacting receptors, and multisystem synapses. The regional characteristics of neuronal architecture, local circuitry, and signaling mechanisms suggest that important aspects of glutamate metabolism are modulated at a local level.¹ Imbalances in glutamatergic neurotransmission and metabolism are proposed as key pathomechanisms in schizophrenia.^1,2N-methyl-d-aspartate receptor hypofunction on γ-aminobutyric acid neurons could result in disinhibition of postsynaptic glutamate neurons, excessive glutamate release, and neurotoxicity. Although excitotoxicity may not be the cause of schizophrenia, it could contribute to the course of the disorder (see Konradi and Heckers³).

To better characterize hippocampal pathophysiology in schizophrenia, we conducted a longitudinal study evaluating hippocampal functional connectivity during resting state, using seeds prescribed in its anterior and posterior regions. We enrolled 34 unmedicated patients with schizophrenia or schizoaffective disorder (SZ) and 34 matched healthy controls. SZ were scanned while off medication, then were treated with risperidone for 6 weeks and re-scanned (n = 22). Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group’s participant level functional connectivity maps. We found significant dysconnectivity with anterior and posterior hippocampal seeds in unmedicated SZ. Baseline connectivity between the hippocampus and anterior cingulate cortex, caudate nucleus, auditory cortex and calcarine sulcus in SZ predicted subsequent response to antipsychotic medications. These same regions demonstrated changes over the 6-week treatment trial that were correlated with symptomatic improvement. Our findings implicate several neural networks relevant to clinical improvement with antipsychotic medications.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, P_FDR<0.05, k_E=2198, x=−30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, P_FDR<0.05, k_E=6094, x=−28, y=−36, z=−2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.