An increasing
level of N-methyl-D-aspartate
(NMDA)receptor
hypofunction within the brain is associated withmemory and learning
impairments, with psychosis, andultimately
with excitotoxic brain injury. As the brain ages,the NMDA receptor system
becomes progressively hypo-functional,
contributing to decreases in memory
andlearning
performance. In those individuals destined todevelop Alzheimer’s
disease, other abnormalities (eg,amyloidopathy
and oxidative stress) interact to increasethe NMDA receptor hypofunction
(NRHypo) burden. Inthese
vulnerable individuals, the brain then enters into asevere and persistent
NRHypo state, which can lead towidespread
neurodegeneration with accompanying men-tal symptoms and further
cognitive deterioration. If thehypotheses
described herein prove correct, treatmentimplications may be
considerable. Pharmacological meth-ods
for preventing the overstimulation of vulnerable cor-ticolimbic pyramidal
neurons developed in an animalmodel
may be applicable to the prevention and treat-ment of Alzheimer’s
disease.The
amino acid glutamate (Glu) plays a centralrole in both the normal
and abnormal functioning ofthe
central nervous system (CNS). Glu is recognized tobe the main excitatory
neurotransmitter in the CNS,estimated
to be released at up to half of the synapses inthe brain. In
addition, Glu is also an excitotoxin that candestroy CNS neurons
by excessive activation of excita-tory
receptors on dendritic and somal
surfaces. Twomajor
classes of Glu receptors, ionotropic
andmetabotropic, have
been identified. Glu exerts excito-toxic activity through
three receptor subtypes, whichbelong
to the ionotropic family. These three receptorsare named after agonists
to which they are differentiallysensitive, N-methyl-D-aspartate
(NMDA), amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA),and
kainic acid (KA). Of these three, the NMDA recep-tor has been the most
extensively studied and the mostfrequently
implicated in CNS diseases.1Excessive activation
of NMDA receptors (NMDAreceptor hyperfunction
[NRHyper]) plays an importantrole
in the pathophysiology of acute CNS injury syn-dromes such as hypoxia-ischemia, trauma, and
statusepilepticus.1,2 Recently, hyperstimulation
of AMPA/KAreceptors
and consequent excitotoxicity has been pro-posed to underlie neurodegeneration
in amyotrophiclateral
sclerosis (ALS, Lou Gerhig’s Disease3,4).The
roleof
Glu excitotoxicity in the pathology of several otherneuropsychiatric disorders
has been extensivelyreviewed elsewhere1,5 and
will not be the focus of thispaper. Instead, we
will focus on the consequences ofunderexcitation
of NMDA receptors (NMDA receptorhypofunction
[NRHypo]).NMDA
receptor function, memory,and
brain agingJohn
W. Newcomer, MD; Nuri B. Farber, MD;John W. Olney, MDKeywords:
Alzheimer’s disease; brain aging; memory; NMDA receptor;
NMDA receptor hypofunction
Author affiliations:Department
of Psychiatry, Washington University School of Medicine, St Louis,
Mo, USA Address for correspondence:
John W. Newcomer, MD, Department of Psychiatry,
Washington University School of Medicine, 4940 Children’s
Place, St Louis, MO 63110-1093, USA
(e-mail: Newcomer@psychiatry.wustl.edu) 2 1 9B a s i c
r e s e a r c h
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