Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease?

Excitatory neurotransmission at many CNS synapses depends upon AMPA-type glutamate receptors. Derangements in AMPA receptor-mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Drugs that positively modulate AMPA receptors by reducing AMPA receptor desensitization and/or slowing AMPA receptor deactivation, such as thiazide derivative (cyclothiazide, diazoxide, IDRA 21) and benzoylpiperidine derivatives (1-BCP, CX516, aniracetam), facilitate AMPA receptor-mediated processes and may have beneficial therapeutic effects. For example, AMPA modulators facilitate long-term potentiation, which may be important for memory storage, and facilitate memory encoding in behavioral experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease. However, AMPA receptor-mediated excitotoxicity may occur with excessive AMPA receptor activation such as in seizures or ischemia, and positive AMPA modulators would promote neuronal injury under those conditions. Regardless of the ultimate clinical utility of positive AMPA modulators, their discovery and study have already provided significant insight into the physiology and structural determinants of important AMPA receptor properties. This review attempts to synthesize a variety of studies that have utilized these AMPA modulators to gain insight into fundamental as well as clinically relevant AMPA receptor-mediated processes.