. Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18163-8. PubMed.

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  1. The intriguing study by Wu et al. provides a clear link between AMPA receptors, the major neurotransmitter receptor for rapid excitatory transmission in the brain, and specific genetic forms of mental retardation. The type of AMPA receptor examined, termed GluR3, is encoded by a gene on the X chromosome, and the authors found several different mutations in GluR3 associated with mild cognitive impairment which likewise influence receptor levels or electrophysiological properties. Since regulation of AMPA receptors contributes to synaptic plasticity and diverse kinds of behavioral learning, this connection is a logical one. It points to GluR3 as an important receptor for learning and memory.

    It is also interesting to note that disorders of cognitive impairment, including Alzheimer disease, have been recently linked to altered function of AMPA receptors at glutamatergic synapses, particularly in the hippocampus. It remains to be determined whether the genetic forms of cognitive impairment linked to mutations in GluR3 represent similar changes in synapse or circuit function as those attributed to Aβ exposure during AD. But clearly, further understanding the function and regulation of AMPA receptors holds promise for revealing the molecular basis for cognitive impairment and mental retardation, and thus for devising new therapeutic strategies.

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