**2. Glutamate hypothesis of schizophrenia**

**1. Introduction**

2 Schizophrenia Treatment - The New Facets

substance abuse [1].

tal cortex [2, 4].

Schizophrenia is a chronic mental disorder that afflicts approximately 1.1% of the population worldwide. Patients not only experience physical and mental disabilities, but also impose a large financial burden that consumes an estimated over \$60 billion in costs per year, including

Schizophrenic patients exhibit an array of clinical symptoms that consist of positive symp‐ toms, negative symptoms, and cognitive impairments. Due to the heterogeneity in symp‐ tomatology, this disorder is difficult to diagnose and treat. Typically, the onset of symptoms occurs between adolescence and early adulthood, mostly within the age range of 16–30 years old, occurring in men (average 18) earlier than women (average 25). Cognitive and social deficits are the first symptoms to appear and exacerbate over time. Individuals display a lack of attention, short‐term and long‐term memory loss, as well as lack of executive functions that include disorganized thoughts and planning. In addition, patients have difficulties commu‐ nicating ideas and notions, consequently leading to social withdrawal. As the individual gets older, negative symptoms appear, including a blunted affect of normal behavior and feelings. For instance, patients will express a lack in motivation and/or pleasure that often leads to depression and mood swings. Positive symptoms develop later and signify an escalated state of mind and altered reality, such as hallucinations, delusions, and false ideas. The amalgama‐ tion of these symptoms persist into adulthood and may perhaps lead to other comorbidities such as attention deficit hyperactive disorder (ADHD), depression, anxiety, aggression, and

Unfortunately, schizophrenia is challenging to diagnose due to the various signs and symp‐ toms; however, neuroanatomical evidence displays structural aberrations in specific tis‐ sues that assist in characterizing the disorder. For instance, postmortem patients show an overall decrease in brain volume and more specifically reduced cortical gray matter in fore‐ brain tissue, such as the dorsolateral prefrontal cortex (dlPFC), superior temporal gyrus, and limbic areas (i.e., hippocampal formation, anterior cingulate cortex). Other anatomi‐ cal anomalies include enlarged cerebral ventricles, such as the lateral and third ventricles. Lastly, at the cellular level, there are reports of reduced neuronal number and dendritic spine densities in the hippocampus and dorsolateral prefrontal cortex [2, 3], although this observation appears to be controversial. Nevertheless, numerous studies have confirmed a significant decrease in pyramidal dendritic spines within superficial layers of the prefron‐

The neurophysiological changes are equally as detrimental as the structural changes observed in schizophrenic patients. For example, the most prevailing theories describing the etiology of schizophrenia is the "Dopamine hypothesis," which predicts dopamine imbal‐ ances within the mesocortical and mesolimbic pathways underlie schizophrenia pathology. Specifically, dopamine deficiency from mesocortical projecting neurons to the prefrontal cortex results in "hypostimulation" of D1‐receptor neurons that contribute to the negative symptoms and cognitive impairments. In contrast, an excess of dopamine to the prefrontal

more than \$20 billion in treatment in the United States of America alone.

Glutamate is an excitatory neurotransmitter that can act on four major classes of receptors, which are either metabotropic or ionotropic. Metabotropic receptors are G‐protein coupled receptors. Metabotropic glutamate receptors are composed of mGluR1‐8 subunits and have seven transmembrane segments that are connected to heterotrimeric G proteins. The remain‐ ing three classes are ionotropic receptors, or ion‐gated channels, that consist of NMDA, AMPA, and kainite receptors, which are readily distinguished by agonists, antagonists, kinet‐ ics, and permeability. Ionotropic glutamate receptors are composed of a tetramer of four subunits, with each representative monomer consisting of three transmembrane segments, a large extracellular glutamate‐binding domain, and a cytosolic loop that lines the channel pore (**Figure 1**).

NMDA receptor hypofunction has long been proposed as one of the major hypothesis for the pathophysiology of schizophrenia [6]. NMDA receptors are highly abundant within the forebrain and are responsible for regulating a variety of neuronal pathways; theoretically, damage to the glutamatergic system could underlie many pathologies of the central nervous system. Accordingly, there is an overwhelming amount of evidence illustrating that NMDA receptor dysfunction contributes to the neurophysiology associated with schizophrenia [6, 7]. For instance, in postmortem subjects with schizophrenia, disruptive mutations of NMDA receptor subunits were revealed in the prefrontal cortex, hippocampus, and thalamus [8, 9]. Furthermore, it is well established that administering noncompetitive NMDA receptor antag‐ onists such as phencyclidine (PCP), MK‐801 (also known as Dizocilpine), and ketamine can mimic the pathophysiology and behavioral attributes of schizophrenia [10–12]. Therefore, treatments that target to improve NMDA receptor function demonstrate an alleviation of

**Figure 1.** Illustration of prototypic ionotropic receptor subunit. A subunit consists of a large extracellular N‐terminus domain, a membrane spanning segment (TM1), a segment that partially enters the membrane (TMII), a glutamate‐ binding domain, two more membrane spanning segments, and an intracellular c‐terminus.

schizophrenic symptoms [13, 14]. Finally, genes implicated in schizophrenia have strong associations with NMDA receptor regulation [15–17].
