Ionotropic glutamate receptors & CNS disorders

Abstract

Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although aetilogy is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual's susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor (AMPAR) trafficking are important to fragile X mental retardation and ectopic expression of kainate receptor (KAR) synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms.

Figure 1. CNS DISORDERS ARE COMPLEX PSYCHIATRIC CONDITIONS

Multiple factors predispose the developing and adult CNS to disease. This axis includes defects in glutamatergic and GABAergic neurotransmission, neuromodulation by other transmitter systems such as dopaminergic and cholinergic, genetic and epigenetic factors. Although the contribution of each predisposing factor may vary depending on the disease state, in most cases, all can negatively impact the prognosis.

Figure 2. CNS DISORDERS ARE TREATED BY TARGETING THE SYMPTOMS

A list of most of the major CNS disorders that afflict society and the drugs commonly used to treat them. Despite advances in our understanding of the CNS, most conditions are treated by attempting to alleviate symptoms rather than tackling the root cause of the disease.

Figure 3. DISCOVERY TIMELINE HIGHLIGHTS MAJOR ADVANCES AND TRENDS IN UNDERSTANDING IONOTROPIC GLUTAMATE RECEPTORS

Although the amino acid, L-Glu, was identified by Ritthausen almost 150 years ago, neurophysiologists in the 1950s ardently debated whether it played any role at all as a neurotransmitter in the CNS. However, early work by Hayashi (1953) and Krnjevič & Philis (1963) lead the way as other groups, particularly Jeffrey Watkins and colleagues, identified selective agonists and antagonists. This work, in turn, permitted the distribution of different iGluR families to be mapped out in the CNS. During the 1980s–90s, cloning studies and advances in understanding the prominent role of iGluRs in synaptic plasticity precipitated an influx of biomedical researchers into the iGluR field which has sustained a comprehesive and ongoing analysis of their function in the CNS.

Figure 4. IONOTROPIC GLUTAMATE RECEPTORS FULFILL DISTINCT ROLES IN THE CNS

Summary table identifying each iGluR subfamily (left column) with the individual subunits that assemble as mature receptors (middle column) and their respective roles within the CNS (right column).

Figure 5. AMPA RECEPTORS AND CNS DISORDERS

Table listing a number of disease states (left column) where defective signaling through AMPARs has been established. The middle column summarizes key characteristics associated with each disorder and the right column refers to the drug classes whose actions may have therapeutic value.

Figure 6. KAINATE RECEPTORS AND CNS DISORDERS

Summary table identifying which KAR subunits are implicated in distinct disorders of the CNS. As work progress, it is likely that this information will be more complete. For example, it is commonly assumed that native KARs are heteromers assembled from GluR5–7 subunits with KA1 and/or KA2. In view of this, in disease states where GluR5–7 have been implicated, it is possible that future work will also implicate KA1 and/or KA2 subunits.