**1. Introduction**

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

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 substance abuse [1].

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‐ tal cortex [2, 4].

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 cortex and striatum from mesolimbic dopamine pathways induces "hyperstimulation" of D2‐receptor neurons, responsible for the positive symptoms [5]. Therefore, current treat‐ ments target dopamine receptors, but leave other pathophysiological mechanisms untar‐ geted. Typical and atypical antipsychotics, such as haloperidol and clozapine, respectively, block D2‐receptors to alleviate psychotic symptoms. However, dopamine‐specific targeted therapy is insufficient to relieve other aspects of the disease; therefore, additional neuronal systems are likely involved.

In recent years, evidence has linked glutamatergic and GABAergic systems to the pathology of schizophrenia. An emerging hypothesis of schizophrenia suggests that N‐methyl‐D‐aspar‐ tate (NMDA) receptor hypofunction plays a major role in the dysregulation of GABAergic transmission, thereby contributing to the symptoms [6]. In this chapter, we discuss the struc‐ ture and function of NMDA and gamma‐aminobutyric acid (GABA) receptors, including the effects of genetic abnormalities on them and their associated posttranslational modifications and signal transduction pathways. We will also include the reviewed literature describing the multiple neuronal subtypes and circuits involved in schizophrenia and potential thera‐ peutic options.
