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Roberto Malinow "Receptor trafficking in synaptic function and dysfunction"

Abstract :

AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits.
Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/ GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.
To identify changes that occur in the brain during learning, we investigated the role of AMPA receptors in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. We find that fear conditioning drives AMPA receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, the encoding of memories in the lateral amygdala appears to be mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy.
Beta amyloid is a peptide generated by neurons and widely believed to underlie the pathophysiology of Alzheimer's Disease when overproduced. Recent studies indicate this peptide can drive endocytosis of AMPA and NMDA type glutamate receptors. We now show that beta amyloid ?employs signaling pathways of LTD to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is key, as it is necessary and sufficient to drive loss of dendritic spines and synaptic NMDA responses. Our results indicate that increased levels of beta amyloid tap into endogenous physiological processes to depress synaptic structure and function.

Selected publications

Kopec CD, Li B, Wei W, Boehm J, Malinow R.
Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation.
J Neurosci. 2006 Feb 15;26(7):2000-9.
PMID: 16481433
Barria A, Malinow R.
NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII.
Neuron. 2005 Oct 20;48(2):289-301.
PMID: 16242409
Rumpel S, LeDoux J, Zador A, Malinow R.
Postsynaptic receptor trafficking underlying a form of associative learning.
Science. 2005 Apr 1;308(5718):83-8. Epub 2005 Mar 3. PMID: 15746389
Ehrlich I, Malinow R.
Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity.
J Neurosci. 2004 Jan 28;24(4):916-27.
PMID: 14749436

Laurent Groc