**10. Glutamate‐GABA association in schizophrenia**

to a reduction in NMDA receptor current [46]. AKT phosphorylation is a negative regulator of GSK3β activity; similarly, GSK3β phosphorylation induces beta‐catenin degradation. High‐ risk genes such as DISC1, dysbindin and NRG1 are all modulators of the AKT‐GSK3β signal‐ ing pathway [34]. For instance, reduced DISC1 protein expression causes a decrease in AKT phosphorylation, and thus an increase in GSK3β activity [47]. In addition, reducing GSK3β activity can alleviate the behavioral impairments observed in DISC1 mouse models [48, 49]. These data suggest a link between high‐risk schizophrenia genes and intracellular pathways, such as the AKT‐GSK3B signaling pathway, that regulate neuronal plasticity. Theoretically, it can be assumed that the high‐risk schizophrenia genes would affect the AKT‐GSK3β sig‐ naling pathway, and thus cause NMDA receptor dysfunction, leading to aberrant neuronal systems that are responsible for the positive, negative, and cognitive symptoms observed in

Typically, drug treatment for schizophrenia patients consists of antipsychotics, such as clo‐ zapine, that target D2 receptors to relieve the positive symptoms. However, a significant portion of schizophrenia subjects do not respond well to D2 antagonists; moreover, the nega‐ tive and cognitive impairments are barely affected by treatment with antipsychotic drugs. As a result, medical professionals are testing new pharmacological agents that target NMDA receptors as a therapeutic option. Due to the observed glutamate hypofunction impairment in patients, investigative studies have focused on the enhancement of NMDA receptor function. Therefore, high doses of glycine agonists (60 g/day) that act upon the glycineB modulatory site are used to increase NMDA receptor function [13]. These agonists have been shown to mod‐ estly improve the negative and positive symptoms of schizophrenia and are currently being utilized as an adjunctive treatment to primary therapy with D2 antagonists. An alternative option is to target the glycine transporter‐1 (GlyT‐1) with the selective inhibitor, sarcosine, to increase glycine availability for NMDA receptor binding [14]. Sarcosine administered at 2 g/day have shown to improve negative and cognitive symptoms of schizophrenia. Other drugs include *d*‐Serine and *d‐*amino acid oxidase (DAAO) inhibitors to increase *d*‐Serine availability, as it is considered a co‐agonist to NR1. The effects of the inhibitor were shown to alleviate negative and cognitive impairments in patients when administered at high doses (>2 g/day) and as a supplement to antipsychotic treatments [14]. Kynurenine aminotransfer‐ ase II (KATII) inhibitors are used to block kynurenic acid (an endogenous antagonist at the NR1 glycineB site) used to improve negative symptoms. NR2 subtype selective modulators are still under drug development and could prove beneficial to a neurological disorder, such as schizophrenia. Other pharmacological drugs available that affect glutamate transmission are utilized to target AMPA receptors, mGlu5 receptors, and NMDA receptors on GABAergic interneurons. However, many of these new therapeutic interventions are still in clinical trials, whether they are more effective than the typical and atypical D2‐related antipsychotic drugs

schizophrenia.

8 Schizophrenia Treatment - The New Facets

remains to be determined.

**9. Drug treatment that targets NMDA receptors**

It is theorized that NMDA dysfunction in neuronal subtypes of GABAergic and dopaminergic neurons collectively contribute to the neuropathologies of schizophrenia. More specifically, investigators speculate that NMDA receptor hypofunction occurs on GABA interneurons (see **Figure 1** in [6]). Glutamatergic neurons have direct interaction with GABA interneu‐ rons, such as basket and chandelier cells, within the cortico‐limbic circuitry. These inter‐ neurons are responsible for suppressing output from glutamate‐releasing pyramidal cells, and due to recurrent collaterals from the two cell types, causes an inhibitory feedback loop. However, if GABAergic activity were suppressed, due to NMDAR dysfunction, it would lead

**Figure 3.** Cross‐connections between NMDA receptors, GABAergic neurotransmission, and PFC‐dependent cognition. PFC persistent neuronal firing is the foundation of working memory with NMDA receptor activity playing a substantial role in this process [50, 51]. NMDA antagonism in conscious behaving monkeys impairs prefrontal‐dependent working memory [52] and induces cognitive impairments in healthy human subjects [11, 53–56], demonstrating a parallel between NMDA hypofunctioning and cognition deficits. This 'online' persistent neural activity is critical for working memory, which is not only NMDAR‐dependent, but also requires fast and synchronous inhibition of prefrontal pyramidal neuronal networks by GABAergic interneurons. GABAergic neurotransmission ultimately drives working memory function through the shaping and synchronization of pyramidal cell output. PV cortical interneurons are especially fundamental for generating fast gamma oscillations, which has been demonstrated in humans to be necessary for proper working memory [57]. NMDARs and GABAergic interneurons are interrelated because NMDA receptors play a large role in the maturation [58] and maintenance of interneurons, especially the NR2A subunit [59].

to disinhibition of pyramidal neurons and excessive firing within the cortico‐limbic circuit. Physiologically, the excitotoxicity could have multiple effects on circuitry such as changes in membrane potential, receptor desensitization, or cell death. These results would have a twofold effect; first, the GABAergic downregulation would lead to negative symptoms and cognitive deficits. And second, the resulting excess glutamate release of cortico‐pyramidal neurons could activate dopaminergic systems that lead to positive symptoms and further cognitive impairments. The glutamate‐GABA systems in the forebrain, especially prefrontal cortex, are intertwined to produce prefrontal‐dependent cognitive function, as proposed in **Figure 3**. Still, how these two systems interact to induce phenotypes and symptoms in schizo‐ phrenia remains to be determined.
