From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment

Abstract

Glutamate is the primary excitatory neurotransmitter in mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimer's disease, and autism-spectrum disorders. Glutamatergic theories of schizophrenia are based on the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex. Based on this mechanism, normalizing excess glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to potential identification of the first non-monoaminergic target with comparable efficacy as conventional antipsychotic drugs for treating positive and negative symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that are active targets for drug development, several of which show promise in preclinical/early clinical trials targeting both symptoms and cognition. To date, most studies have been done with orthosteric agonists and/or antagonists at specific sites. However, allosteric modulators, both positive and negative, may offer superior efficacy with less danger of downregulation.

Figure 1

One of the downstream consequences of NMDAR inhibition is increased availability of glutamate (see text and Figure 2 for potential mechansims that can cause this effect). This increase causes excess activity of AMPA receptors and enhanced postsynaptic spiking of cortical principle cells at rest.

Figure 2

(a) Principal (P) or pyramidal cells in the neocortex and hippocampus, all which use glutamate as their neurotransmitter, receive extensive excitatory input from subcortical and cortical regions. In the absence of a counteracting inhibitory influence, activation of these inputs could cause a chain reaction of ever increasing excitation. (b) The regulation or stabilization of the firing of pyramidal cells is served by GABA (G) interneurons. One classic example of GABAergic influence is the feed-forward inhibition model where the effect of afferent excitation on a pyramidal neuron is dampened by co-activation of GABA interneurons that synapse onto the same pyramidal neuron. (c) The excitatory–inhibitory balance can be disrupted by many factors. An example is exposure to pro-psychotic compounds such as NMDA receptor antagonists. Blockade of NMDA receptors preferentially acts on fast spiking GABA interneurons because these neurons have a more depolarized membrane potential (note the higher firing rate on the recording from a putative GABA interneuron in the prefrontal cortex of an awake rat) and thus contain more open NMDA channels. This preferential inhibition of GABA interneurons creates an artificial state of disinhibition for the pyramidal cells and increases their firing rate.

Figure 3

A simplified model of glutamate (Glu) synapse depicting some of the potential targets for manipulating the function of NMDA receptors. The two primary subunits of the receptor (NR1 and NR2) are depicted. On the presynaptic side, excess release of glutamate can be reduced by metabotropic group 2 receptors. Levels of vesicular glutamate also can be manipulated by the activity of the synthetic enzyme glutaminase, which converts glutamine (Gln) to Glu. On the postsynaptic site, several regulatory sites on the NMDA channel itself (eg, magnesium and PCP-binding sites, the D-serine and glycine (Gly) site and the redox (glutathione)) regulate the function of the receptor. In addition, other membrane-spanning receptors, such as the metabotropic group 5 (mGlu5) receptor or the ErbB4 receptor, indirectly influence the function of NMDAR by interacting through postsynaptic density (PSD) or signal transduction mechanisms. The glia includes a large number of proteins that influence both presynaptic and postsynaptic function of this synapse. These include transporters for both Glu and Gly, the D-serine-synthesizing enzyme serine racemase, D-serine transporter, as well as cystine–Glu transporter. In addition, a number of metabotropic Glu receptors including mGluR3 and mGluR5 are expressed by glia.

Figure 4

Allosteric modulation of receptors can selectively modulate active synapses. Under normal conditions, postsynaptic receptors are activated phasically when an action potential releases neurotransmitter from presynaptic terminals. A suboptimal activation of these receptors in a disease state is better treated with an allosteric positive modulator (PAM) that enhances the function of the natural neurotransmitter on those receptors as opposed to an agonist that produces constant activation of receptors. The latter could lead to desensitization of receptors, neurotoxicity, and other side effects.