Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.

Many drugs of abuse exert their addictive effects by increasing extracellular dopamine in the nucleus accumbens, where they likely alter the plasticity of corticostriatal glutamatergic transmission. This mechanism implies key molecular alterations in neurons in which both dopamine and glutamate inputs are activated. Extracellular signal-regulated kinase (ERK), an enzyme important for long-term synaptic plasticity, is a good candidate for playing such a role. Here, we show in mouse that d-amphetamine activates ERK in a subset of medium-size spiny neurons of the dorsal striatum and nucleus accumbens, through the combined action of glutamate NMDA and D1-dopamine receptors. Activation of ERK by d-amphetamine or by widely abused drugs, including cocaine, nicotine, morphine, and ⌬ 9 -tetrahydrocannabinol was absent in mice lacking dopamine-and cAMP-regulated phosphoprotein of M r 32,000 (DARPP-32). The effects of d-amphetamine or cocaine on ERK activation in the striatum, but not in the prefrontal cortex, were prevented by point mutation of Thr-34, a DARPP-32 residue specifically involved in protein phosphatase-1 inhibition. Regulation by DARPP-32 occurred both upstream of ERK and at the level of striatal-enriched tyrosine phosphatase (STEP). Blockade of the ERK pathway or mutation of DARPP-32 altered locomotor sensitization induced by a single injection of psychostimulants, demonstrating the functional relevance of this regulation. Thus, activation of ERK, by a multilevel protein phosphatase-controlled mechanism, functions as a detector of coincidence of dopamine and glutamate signals converging on medium-size striatal neurons and is critical for long-lasting effects of drugs of abuse.dopamine D1 receptor ͉ drug addiction ͉ NMDA receptor ͉ nucleus accumbens ͉ protein kinase M any drugs of abuse share the ability to stimulate dopamine transmission in the nucleus accumbens (1). They are thought to mimic the effects of naturally reinforcing stimuli and divert the normal role of dopamine neurons in coding reward prediction errors (2). Dopamine modulates long-term depression and potentiation at glutamatergic corticostriatal synapses, and current models of striatal circuits suggest that the regulation of the plasticity of corticostriatal transmission is a central mechanism of dopamine-controlled-learning (3, 4). One prediction of these models is that key biochemical events should occur specifically in neurons in which both dopamine and glutamate inputs are activated. Activation of extracellular signal-regulated kinase (ERK) is a candidate for such a role because it depends on both dopamine and glutamate receptors (5). In addition, ERK activity is known to be important for long-term synaptic plasticity (6), and its pharmacological blockade prevents the transcriptional and rewarding effects of cocaine and ⌬ 9 -tetrahydrocannabinol (THC) (5, 7). To determine the role of ERK in the long-term action of dopamine in the striatum, it is critical to identify in which neurons it is activated and the mechanism of this activation. In ...