Novel approaches to estimate prefrontal synaptic strength in vivo in humans: of relevance to depression, schizophrenia, and ketamine

Synaptic strength, defined as the magnitude of the postsynaptic response to a presynaptic action potential, is essential in the creation and adaptation of brain networks and plays a critical role in mental health and illnesses. Converging preclinical evidence indicate loss of glutamatergic synaptic strength in various paradigms of chronic stress and depression. A major challenge in the field is to implement a reliable approach to estimate overall glutamatergic synaptic strength within a brain region in vivo in humans to determine its role in the pathophysiology and treatment of depression and other neuropsychiatric disorders.

Dynamic carbon-13 magnetic resonance spectroscopy (¹³C MRS) is a unique imaging technique that can provide estimates of two measures directly related to glutamatergic synaptic strength: (1) the rate of glutamate neurotransmission cycling (V_Cycle) and (2) the rate of neuronal oxidative energy production (V_TCAn) [1]. Considering the tight coupling between synaptic signaling and brain energetics [1], the ratio of V_TCAn/V_Cycle, which is Energy Per Cycle (EPC), was proposed as a putative biomarker of glutamatergic synaptic strength [2]. Notably, EPC is highly conserved across species and is very stable in differing mental state from fully awake to fully anesthetized [1]. To our surprise, approximately a decade ago, we found a remarkable 26% reduction in cortical EPC in patients with major depressive disorder (MDD) compared to healthy controls, consistent with preclinical evidence of reduced synaptic strength in depression pathology [2].

Ketamine, an N-methyl-D-aspartate receptors (NMDAR) antagonist, is known to both block NMDAR transmission and paradoxically increase presynaptic glutamate release [3]. Thus, ketamine administration offers a distinctive paradigm of pharmacologically induced transient reduction in glutamatergic synaptic strength. Preclinical ¹³C MRS studies support the presence of ketamine-induced reduction in glutamatergic synaptic strength [4]. To extend these preclinical findings to humans, we investigated the effects of subanesthetic ketamine on prefrontal ¹³C enrichment during ¹³C-glucose infusion in healthy and MDD participants [5]. Immediately following ketamine administration, we found a significant reduction in glutamatergic synaptic strength, as estimated by EPC [5]. These transient effects of ketamine on prefrontal glutamate neurotransmission are believed to induce prefrontal synaptic growth and rapid acting antidepressant effects 24 h posttreatment [3, 6]. Intriguingly, the magnitude of ketamine-induced reduction in prefrontal EPC during infusion was significantly associated with the psychomimetic effects of the drug, a human paradigm to recapitulate core symptoms of psychosis [5]. The latter finding suggested that psychosis pathology in schizophrenia may not necessarily be solely related to disruption in glutamate release, but rather a loss of communication fidelity between presynaptic signaling and postsynaptic activation [5].

Together, these data underscore the essential role of prefrontal synaptic strength in the pathology of psychiatric disorders. The evidence also demonstrates the robustness and utility of EPC, measured by ¹³C MRS, as valid biomarker of glutamatergic synaptic strength. Future studies will determine the pattern of EPC disruption across disorders and its response to rapid acting antidepressants, such as ketamine.