Synaptic fidelity for drug development: Is it time to move beyond glutamate release and receptors?

KEYWORDS:

• glutamate
• schizophrenia
• MRS
• synaptic fidelity
• density
• strength
• ketamine
• NMDA
• energy per cycle

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1.0 Introduction

Schizophrenia pathophysiology has been mainly attributed role of dopamine receptor antagonism, with antipsychotic drugs targeting this mechanism. However, a proportion of individuals with schizophrenia do not respond to these drugs, and these drugs have limited benefit for negative symptoms in chronic schizophrenia leading to the investigation of other neurotransmitters that may interact with dopamine in schizophrenia. Dopamine is bi-directionally implicated in inflammatory processes with effects on post-synaptic density needed for N-methyl-D-aspartate glutamate receptor (NMDAR) function [1]. The role of glutamate in schizophrenia and other psychiatric disorders is further implied by the ubiquity of this neurotransmitter in the brain; carbon-13 magnetic resonance spectroscopy (¹³C MRS) has shown a close relationship between glutamatergic neurotransmission and energy metabolism in the brain (consisting of approximately ¾ of total glucose consumption in the brain)[2]. Collectively compelling and strong empirical research over the last three decades further supports the role of glutamate signaling in the pathophysiology schizophrenia, [3–6] (see review [5]). Yet, the research focus on glutamate release and receptors have not yielded to date the anticipated novel treatments. For example, glutamate-based drug development for schizophrenia have failed in larger trials targeting N-methyl-D-aspartate receptors (NMDAR) or glutamate release [7]. Some have attributed these failures to methodological limitations of imaging the glutamate system and the heterogeneity of schizophrenia disorder [5]. Adding to these explanations, here we suggest that it is time for the field to move beyond narrow lens on glutamate release and receptors to shift focus towards holistic neuroenergetics and glutamate signal processing [5]. We specifically focus on synaptic fidelity, the degree of accuracy of synaptic signal processing of a presynaptic input, which may be measured using carbon-13 magnetic resonance spectroscopy.

2.0 Why should we target synaptic fidelity?

Synaptic fidelity is the postsynaptic outcome of a presynaptic signal under normal conditions; that is, the degree of accuracy of the synaptic signal processing of a presynaptic input. This characteristic represents a converging pathway for normal brain functioning and the various glutamate impairments identified in psychiatric disorders. Consequently, synaptic fidelity should be the target of biomarker identification and drug development. Numerous factors may disrupt synaptic fidelity. For example, both iatrogenic blockade of postsynaptic receptors or induction of large presynaptic neurotransmitters release can overload the synaptic signal processing and affect synaptic fidelity. For simplicity, synaptic fidelity can be divided chronologically into its immediate and distant response. Immediate synaptic fidelity is primarily assessed by measuring synaptic strength, indicating the amount of postsynaptic activation in response to a presynaptic action potential. Distant synaptic fidelity includes the ‘electrically silent’ adaptation of the synaptic complex that affects the response to future presynaptic input. This synaptic plasticity involves synaptic scaling, long-term depression/potentiation, and changes in synaptic density within a brain region. In this brief viewpoint, we will describe available biomarkers of synaptic fidelity in vivo in humans, review pilot evidence relating psychopathology to synaptic fidelity using schizophrenia as a case example and propose future directions to integrate findings and advance this line of research.

3.0 How do we non-invasively study biomarkers of synaptic fidelity?

Considering the ubiquity of glutamate synapses and their role in neuronal signaling, it is not surprising that most functional brain imaging techniques are, at least indirectly, affected by glutamate synaptic neurotransmission. For example, fluorodeoxyglucose positron emission tomography is reflective of the association between brain metabolism and neuronal postsynaptic activation. Other methods may better reflect presynaptic transmission or overall density of synapses. However, determining synaptic fidelity requires both presynaptic transmission and postsynaptic activation to be measured concurrently.

To date, dynamic ¹³C MRS is the only minimally invasive method that concurrently measures presynaptic glutamate release (V_Cycle) and postsynaptic neuronal activation (V_TCAn) in vivo in humans [8] and can be accomplished using ¹³C-glucose or ¹³C-acetate as stable isotopes. V_Cycle and V_TCAn allow the computation of energy-per-cycle (EPC; which is computed as the ratio of V_TCAn divided by V_Cycle) as biomarker of synaptic fidelity [9]. ¹³C-glucose MRS is more complex but provides separate measures of V_Cycle and V_TCAn. The ¹³C-acetate MRS is simpler, less burdensome and allows the direct computation of V_TCAn/V_Cycle ratio at steady state providing higher signal to noise without requiring kinetic modeling. However, this latter approach does not calculate V_Cycle and V_TCAn independently [10]. Centrally invasive electrophysiological approaches to measure synaptic fidelity are primarily implemented in preclinical studies. In humans, EPC values as measured by 13C MRS have a mean of 0.72 and standard error of mean of 0.03 [11].

4.0 What is the evidence implicating synaptic fidelity in psychiatric disorders?

In the early 1980s, it was found that the dissociative anesthetics phencyclidine (PCP) and ketamine possess NMDAR antagonism properties [7]. This discovery eventually led to the glutamate hypothesis of schizophrenia based on the observations that these dissociative anesthetics mimic various aspects of the positive, negative, and cognitive symptoms of schizophrenia [12]. Informed by evidence showing that ketamine induces paradoxical increase in glutamate release, the ‘disinhibition model’ was later proposed for schizophrenia. It was hypothesized that NMDAR hypofunction on subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons reduces inhibition of pyramidal neurons leading to excessive glutamate release and subsequent psychopathology [12]. This elegant model has guided the schizophrenia glutamate-based drug development for decades. Various compounds that aim to either reduce glutamate release (e.g., targeting metabotropic glutamate receptors type 2) or enhance NMDAR activity (e.g., inhibition of glycine transporter 1) have been extensively investigated [7]. Unfortunately, neither approach has yielded new approved treatments to date.

An alternative model is that PCP and ketamine induce their psychotomimetic effects by disrupting synaptic fidelity in brain regions critical to the pathophysiology of psychosis. In this model, the blockade of postsynaptic NMDARs on pyramidal neurons by ketamine disrupts the information processing at the level of glutamatergic synapses leading to increased noise in the system and subsequent behavioral disturbances. This is further exacerbated by the ketamine-induced glutamate surge, which iatrogenically introduces additional noise perturbing normal synaptic signal processing. Notably, V_Cycle and V_TCAn – putative input and output markers of synaptic fidelity – are strongly coupled under normal conditions and maintain an almost 1:1 ratio across species and differing mental state. Unexpectedly, ¹³C MRS studies examining glutamate dynamics during ketamine infusion compared to normal saline in humans found enrichment changes consistent with increased prefrontal glutamate release (V_Cycle) but no reciprocal changes in postsynaptic activation (V_TCAn). This decoupling between neurotransmission and neuroenergetic needs is consistent with a ketamine-induced disruption in prefrontal synaptic fidelity. Importantly, the psychotomimetic effects of ketamine were negatively associated with prefrontal EPC, indicating reduced synaptic fidelity in participants with the highest dissociative symptoms during ketamine infusion [9].

The synaptic fidelity model of psychosis may shed light on the dose-effect response and on compounds that induces psychotomimetic effects without directly blocking NMDARs. For example, anticholinergic muscarinic antagonists, known to induce psychosis, were found in preclinical ¹³C MRS studies to induce glutamate enrichment changes consistent with reduction in EPC. Intriguingly, the drug-induced reduction in EPC was more pronounced following administration of higher dose ketamine (30mg/kg) compared to 1) low doses of ketamine (3 and 10mg/kg), 2) selective NMDAR subtype 2B antagonists and 3) muscarinic antagonists [13]. Together, this data indicated that less potent psychotomimetic drugs induce less disruption in synaptic fidelity as measured by EPC [9].

5.0 Expert opinion

Glutamate synapses are ubiquitous and possess multiple essential roles in the brain, presenting both a challenge and an opportunity for the field. Hence, we predict that abnormalities in neuroenergetic markers of synaptic fidelity will be common across several disorders. In fact, we have already identified cortical EPC abnormalities in depression [14] and posttraumatic stress disorder [10]. The critical determinant is the location and extent of synaptic fidelity disturbance, which in turn leads to disease-specific network disruptions and subsequent behavioral symptoms. For example, NMDAR hypofunction is one pathway, among many others, to disrupt synaptic fidelity. The disease specific mechanisms may be the downstream network disruptions. Therapeutic approaches may target synaptic fidelity, particularly distal responses that underlie synaptic plasticity. For example, ketamine’s antidepressant effects are thought to be underpinned by NMDA receptor antagonism that impacts intracellular signaling, such as by inducing rapid translation of brain-derived neurotropic factor, in turn triggering downstream synaptic plasticity changes. In evidence, although studies in schizophrenia have yet to be done, ¹³C MRS has been used in humans to show that ketamine increases the glutamate-glutamine cycling [15].

The hope is that by targeting synaptic fidelity holistically, rather than underlying processes of glutamate signal, we may be able to better optimize doses and administration regimen of novel compounds to effectively treat a wider population of patients with perhaps heterogenous abnormalities within the glutamatergic synapse. As a field, we should 1) invest in developing, establishing, and optimizing techniques aimed at assessing synaptic fidelity in vivo in humans; 2) encourage preclinical research and psychopathology models to focus on the glutamatergic synapse function as whole rather than a mix of neurotransmitters and receptors; and 3) investigate the brain circuits and network correlates of localized synaptic fidelity disruptions.

Finally, though the scope of this editorial is limited to the neuroenergetics of glutamate, it is acknowledged that dopamine dysfunction is known to underpin the core psychopathology of schizophrenia. From this core system many others are next implicated: glutamatergic, serotonergic, acetylcholinergic, and GABA alterations. Future work should engage novel methods that can jointly examine in-vivo neuroenergetics of glutamate, GABA, dopamine, and other relevant neurotransmitter systems relevant to schizophrenia to set the foundation for novel drug development[5].

Declaration of interest

C Abdallah has served as a consultant, speaker and/or on advisory boards for Aptinyx, Genentech, Janssen, Psilocybin Labs, Lundbeck, Guidepoint, Douglas Pharmaceuticals, and FSV7, and as editor of Chronic Stress for Sage Publications, Inc. They also filed a patent for using mTORC1 inhibitors to augment the effects of antidepressants (Aug 20, 2018). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Salary support was provided by NIMH (R01MH112668), Department of Veterans Affairs and the Beth K and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome. The content is solely the responsibility of the author and does not necessarily represent the official views of the sponsors, the Department of Veterans Affairs, NIH, or the U.S. Government.