The substrates of memory: defects, treatments, and enhancement.
Recent work has added strong support to the long-standing hypothesis that the stabilization of both long-term potentiation and memory requires rapid reorganization of the spine actin cytoskeleton. This development has led to new insights into the origins of cognitive disorders, and raised the possibility that a diverse array of memory problems, including those associated with diabetes, reflect disturbances to various components of the same mechanism. In accord with this argument, impairments to long-term potentiation in mouse models of Huntington's disease and in middle-aged rats have both been linked to problems with modulatory factors that control actin polymerization in spine heads. Complementary to the common mechanism hypothesis is the idea of a single treatment for addressing seemingly unrelated memory diseases. First tests of the point were positive: Brain-Derived Neurotrophic Factor (BDNF), a potent activator of actin signaling cascades in adult spines, rescued potentiation in Huntington's disease mutant mice, middle-aged rats, and a mouse model of Fragile-X syndrome. A similar reversal of impairments to long-term potentiation was obtained in middle-aged rats by up-regulating BDNF production with brief exposures to ampakines, a class of drugs that positively modulate AMPA-type glutamate receptors. Work now in progress will test if chronic elevation of BDNF enhances memory in normal animals.
Lynch
Gary
G
Department of Psychiatry and Human Behavior, University of California, Irvine CA, United States.
Rex
Christopher S
CS
Chen
Lulu Y
LY
Gall
Christine M
CM
D000199:Actins / Q000502:physiology; D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D049229:Dendritic Spines / Q000502:physiology; D005600:Fragile X Syndrome / Q000503:physiopathology; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D013569:Synapses / Q000502:physiology
D000199:Actins; D019208:Brain-Derived Neurotrophic Factor; D018697:Nootropic Agents