**3. The NMDA receptor structure and function**

NMDA receptors are typically located on excitatory glutamatergic synapses, although present in many cell types (i.e., GABAergic neurons, dopaminergic neurons, etc.). NMDA receptors are responsible for synaptic plasticity and cortical development, as well as cognitive pro‐ cesses such as learning and working memory [18]. NMDA receptors are a heterotetrameric complex that consists of an obligatory homodimer of NR1 and homodimers or heterodimers of either combination of NR2A‐D or NR3A‐D subunits (**Figure 2**). The NMDA channel is voltage‐dependent and ligand‐gated, and highly permeable to Na<sup>+</sup> , K+ , and Ca2+, causing depolarization of a cell and subsequent excitation and activation of intracellular signaling pathways. Although NR1 subunits are required for NMDA receptor function, NR2/NR3 sub‐ units are specialized and critical for functional diversity such as calcium permeability, decay time, open channel time, and pharmacology sensitivity. In addition, NR1 and NR2 subunits The Convergence of Glutamate and GABA Dysregulation in Schizophrenia http://dx.doi.org/10.5772/65870 5

**Figure 2.** Schematic diagram depicting a NMDA receptor complex. Glutamate binds at NR2/NR3 complex and co‐ agonist glycine or D‐serine binds at NR1 complex. Upon depolarization, Mg2+ is removed. NMDA receptor permeates Na+ and Ca+ influx and K<sup>+</sup> efflux upon activation. Binding sites for PCP, ketamine, and MK801 are included (Figure was modified from Snyder et al. [6] and Cioffi et al. [14]).

contain distinct sites that bind glycine, PCP, and Mg2+ that modulate the activity of NMDA receptors (**Figure 2**).

#### **4. The NMDA receptor development**

schizophrenic symptoms [13, 14]. Finally, genes implicated in schizophrenia have strong

**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‐

NMDA receptors are typically located on excitatory glutamatergic synapses, although present in many cell types (i.e., GABAergic neurons, dopaminergic neurons, etc.). NMDA receptors are responsible for synaptic plasticity and cortical development, as well as cognitive pro‐ cesses such as learning and working memory [18]. NMDA receptors are a heterotetrameric complex that consists of an obligatory homodimer of NR1 and homodimers or heterodimers of either combination of NR2A‐D or NR3A‐D subunits (**Figure 2**). The NMDA channel is

depolarization of a cell and subsequent excitation and activation of intracellular signaling pathways. Although NR1 subunits are required for NMDA receptor function, NR2/NR3 sub‐ units are specialized and critical for functional diversity such as calcium permeability, decay time, open channel time, and pharmacology sensitivity. In addition, NR1 and NR2 subunits

, K+

, and Ca2+, causing

associations with NMDA receptor regulation [15–17].

4 Schizophrenia Treatment - The New Facets

**3. The NMDA receptor structure and function**

voltage‐dependent and ligand‐gated, and highly permeable to Na<sup>+</sup>

binding domain, two more membrane spanning segments, and an intracellular c‐terminus.

Developmentally, there is an NR2B‐ to NR2A‐subunit switch that occurs from childhood‐to‐ adulthood in most brain regions that facilitate synaptic maturation [19]. NR2B protein expres‐ sion levels are highly abundant during early development and decline into adulthood; in contrast, NR2A levels begin low and rise in adult. Both subunits are essential for prefrontal synaptic plasticity and function; however, NR2B plays a more dominant role. For instance, in the prefrontal cortex, NR2B levels remain high into adulthood and are important for working memory function [20, 21]. NR2B‐containing NMDA receptors play a major role in calcium (Ca+ ) influx at the postsynaptic membrane, as NR2B receptors have slower kinetics, thus a slower decay time compared to NR2A‐containing NMDA receptors. This indicates that NR2B receptors conduct a large amount of Ca+ and Na+ due to the prolonged open channel state. Although NR2B is essential for cognition processes within the adult, an overabundance may be hazardous due to the significant increase in Ca<sup>+</sup> conductance that could lead to excitotox‐ icity and neuronal death [21]. Therefore, NR2B/NR2A composition during development is extremely critical for normal synaptic maturation.
