The Glutamatergic Hypothesis for Down Syndrome: The Potential Use of N-Methyl-D-Aspartate Receptor Antagonists to Enhance Cognition and Decelerate Neurodegeneration
Alberto C.S. Costa
Affiliation: Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies & Children's Hospital, 11100 Euclid Avenue, Cleveland, Mail Stop RBC 6090. OH 44106, USA.
Down syndrome (DS) is the most common genetically defined cause of intellectual disability and accounts for
over 50% of the cases of Alzheimer-type dementia in persons younger than 50 years of age. At present, no
pharmacotherapy aimed at counteracting either the neurodevelopmental or the neurodegenerative component of this
genetic disorder has been approved. Recent preclinical and clinical work on the N-methyl-D-aspartate (NMDA) receptor
antagonist memantine give us some reason for optimism, at least in relation to the potential for a partial pharmacological
improvement of hippocampus dependent memory deficits associated with DS. Here, we will review briefly the roles of
NMDA receptors in health and disease, including the glutamatergic hypothesis for Alzheimer disease. Then, we will
describe the basis for a glutamatergic hypothesis for DS, by reviewing the available preclinical evidence and assessing
potential molecular mechanisms for NMDA receptor dysfunction in DS. A short description of the first two clinical trials
of memantine in young and older adults with DS will follow. We will conclude by reviewing three caregiver reports from
our recent clinical study and some lessons we have learned designing and conducting the first translational study in the
field of DS to arise directly from experimental results in animal models.
Keywords: Down syndrome, Alzheimer disease, Trisomy 21, Ts65Dn mouse, Memantine, N-methyl-D-aspartate receptor,
Long-term potentiation, Long-term depression.
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