Translating glutamate: from pathophysiology to treatment

Abstract

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autism, and depression-that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration-approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine-sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.

Fig. 1

Schematic diagram of the glutamate synapse. Receptors most amenable to therapeutic manipulation include the AMPA and NMDA-type glutamate receptors; metabotropic type 2, 3, 5, and 7 receptors (mGluR2, mGluR3, mGluR5, and mGluR7); transporters for glutamate (GLT-1); glycine (GlyT1); and the cystine/glutamate antiporter (XC).

Fig. 2

Proposed glutamate-based treatment targets for drug abuse, including cystine/glutamate transporter (XC⁻) and the glutamate transporter (GLT-1). NAC, N-acetylcysteine; LTD, long-term depression. Updated from (32).

Fig. 3

An example biomarker for glutamate-based drug development. (A) MMN is an event-related potential generated in primary auditory cortex. (B to D) Auditory-evoked field potentials (AEP), current source density (CSD), and multiunit activity (MUA) analyses show MMN-related activity in superficial layers of auditory cortex (B) and dose-dependent inhibition by local administration of the NMDAR antagonist PCP (C), leading to a reduction in local summed (SUMREC) current flow (D) (65). (E) In schizophrenia, reductions in MMN generation correlate with overall function, as reflected in the global assessment of function (GAF) score (60). (F) Deficits similar to those observed in schizophrenia are induced in volunteers by acute administration of ketamine (69). (G) Histological investigation of auditory cortex shows reduced glutamatergic pyramidal cell volume, consistent with underlying glutamatergic dysfunction (155). (A) to (D) is reprinted from (65). (E) is reprinted with permission from (60). (F) is reprinted with permission from (69). (G) is reprinted by permission from Macmillan Publishers Ltd. (155), copyright (2009).

Fig. 4

Schematic model of interactive drug development among academia, government, and pharma, designed to overcome barriers to translational drug development. In this model, biomarkers are developed in a precompetitive space, with pharma providing nonproprietary compounds, expertise, and financial support, which is matched by government and foundations. In addition, baseline genetic and consensus behavioral and biomarker data from clinical trials are pooled to permit comparison among disease states and genotype/phenotype investigation.

Fig. 5

(A and B) Effects of the NMDAR antagonist ketamine in unipolar (A) (138) and bipolar (B) depression, showing persistent effect. Adapted from (138) and (140).