Publications (51) View all
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Article: Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression.
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ABSTRACT: The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's disease.Proceedings of the National Academy of Sciences 03/2013; 110(10):4033-8. · 9.68 Impact Factor -
Article: Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression.
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ABSTRACT: NMDA receptor (NMDAR) activation controls long-term potentiation (LTP) as well as long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. A long-standing view proposes that a high level of Ca entry through NMDARs triggers LTP; lower Ca entry triggers LTD. Here we show that ligand binding to NMDARs is sufficient to induce LTD; neither ion flow through NMDARs nor Ca rise is required. However, basal levels of Ca are permissively required. Lowering, but not maintaining, basal Ca levels with Ca chelators blocks LTD and drives strong synaptic potentiation, indicating that basal Ca levels control NMDAR-dependent LTD and basal synaptic transmission. Our findings indicate that metabotropic actions of NMDARs can weaken active synapses without raising postsynaptic calcium, thereby revising and expanding the mechanisms controlling synaptic plasticity.Proceedings of the National Academy of Sciences 03/2013; 110(10):4027-32. · 9.68 Impact Factor -
Article: Neuroscience: Strength in numbers.
Nature 01/2013; 493(7433):482-3. · 36.28 Impact Factor -
Article: Disrupted cortical function underlies behavior dysfunction due to social isolation.
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ABSTRACT: Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.The Journal of clinical investigation 06/2012; 122(7):2690-701. · 15.39 Impact Factor -
Article: Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin.
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ABSTRACT: The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an "antireward" signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin, a neuromodulator implicated in depression.Neuron 05/2012; 74(3):475-81. · 14.74 Impact Factor
