Long-term potentiation (LTP) of synaptic strength, the
most established cellular model of information storage
in the brain, is expressed by an increase in the number
of postsynaptic AMPA receptors. However, the source of
AMPA receptors mobilized during LTP is unknown. We have
demonstrated that transport from recycling endosomes to
the plasma membrane maintains the supply of AMPA receptors
at excitatory synapses and is required for LTP. Surprisingly,
stimuli which trigger LTP, promote not only AMPA receptor
insertion, but also generalized recycling of cargo and
membrane from endocytic compartments. These results identify
recycling endosomes as the source of AMPA receptors for
LTP, and provide an unexpected mechanistic link between
synaptic potentiation and membrane remodeling during synapse
modification.
A key step in glutamatergic synapse maturation is the
replacement of postnatally expressed N-methyl-D-aspartate
receptors (NMDARs) with mature forms which differ in subunit
composition, stably attach to synaptic sites, and are
thought to "solidify" neural circuitry. However, the mechanisms
underlying the removal and replacement of synaptic NMDARs
are poorly understood. We have demonstrated that NMDARs
containing the developmentally regulated NR3A subunit
undergo rapid endocytosis from the dendritic plasma membrane.
This endocytic removal is controlled by the adaptor protein
PACSIN1/ syndapin1, which directly binds the carboxy-terminal
domain of NR3A through its NPF motifs and assembles a
complex of proteins including dynamin and clathrin. Endocytosis
of NR3A by PACSIN1 is activity-dependent, and disruption
of PACSIN1 function causes NR3A accumulation at synaptic
sites. Our results reveal a novel, activity-dependent
mechanism involved in the regulation of NMDAR expression
at synapses during development, and identify an adaptor
that confers spatiotemporal and subunit specificity to
NMDAR endocytosis.
