Regulation of postsynaptic AMPA responses by synaptojanin 1

Abstract

Endocytosis of postsynaptic AMPA receptors is a mechanism through which efficiency of neurotransmission is regulated. We have genetically tested the hypothesis that synaptojanin 1, a phosphoinositide phosphatase implicated in the endocytosis of synaptic vesicles presynaptically, may also function in the endocytosis of AMPA receptors postsynaptically. Electrophysiological recordings of cultured hippocampal neurons showed that miniature excitatory postsynaptic current amplitudes were larger in synaptojanin 1 knockout (KO) neurons because of an increase of surface-exposed AMPA receptors. This change did not represent an adaptive response to decreased presynaptic release in KO cultures and was rescued by the expression of wild type, but not catalytically inactive synaptojanin 1, in the postsynaptic neuron. NMDAinduced internalization of pHluorin-tagged AMPA receptors (GluR2) was impaired in KO neurons. These results reveal a function of synaptojanin 1 in constitutive and triggered internalization of AMPA receptors and thus indicate a role for phosphatidylinositol(4,5)-bisphosphate metabolism in the regulation of postsynaptic AMPA responses.hree classes of ionotropic receptors-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and Nmethyl-D-aspartate (NMDA) receptors-mediate responses to glutamate, the major excitatory neurotransmitter, in the nervous system. AMPA receptors are responsible for most of the fast excitatory synaptic transmission (1). Therefore, alterations in AMPA receptor number and/or function at the synapse are likely to play an important role in synaptic plasticity and in learning and memory. AMPA receptors cycle constitutively by exoendocytosis between intracellular and surface-exposed pools, and the regulation of this cycle by signal molecules or synaptic activity allows for fast and effective control of receptor number on the postsynaptic membrane (2-5). For example, an increased number of surface-exposed AMPA receptors is a mechanism underlying long-term potentiation. Conversely, long-term depression may involve endocytosis of these receptors to reduce synaptic strength (2-4).Both constitutive and regulated AMPA receptor endocytosis were shown to be dependent on clathrin, the clathrin adaptors, and dynamin (3, 5-9). Thus, clathrin-mediated endocytosis, a process known to play a fundamental role in the recycling of synaptic vesicles (10, 11), also has a critical role postsynaptically, although the flux of endocytic traffic is much more intense presynaptically. Accordingly, a growing number of components of the clathrin-dependent endocytic machinery of the presynapse were reported, by either morphological or functional studies, to be present also at the postsynapse (8,9,12,13). One protein that is expressed at high levels in the nervous system and is concentrated in nerve terminals, where it has an important role in the clathrin-dependent recycling of synaptic vesicles, is synaptojanin 1 (SJ1) (14-17).SJ1 is a polyphosphoinositide phosphatase that mediates phosphatidylinositol(4...

PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression

“…In conclusion, we have identified a unique interaction between PICK1 and the endocytic protein PACSIN and have shown that their phosphorylation-regulated interaction is required for the activity-dependent trafficking of GluA2-containing AMPARs and the expression of cerebellar LTD. Our data also provide further evidence supporting the functional duality of presynaptic trafficking machinery, such as the lipid phosphatase, synaptojanin1 (49), and the exocytic protein, complexin1 (50), in regulating the trafficking of AMPARs on the postsynaptic membrane and synaptic plasticity.…”

Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2

“…In the absence of CPG2, clathrin-coated vesicles accumulate in the postsynaptic compartment (11), suggesting that CME coupling to the cytoskeleton is required for vesicle uncoating. Loss of Synaptojanin, a protein known to promote endocytic vesicle uncoating, like loss of CPG2, also leads to increased AMPAR surface expression as well as impaired constitutive and NMDA-induced internalization of AMPARs (21). Actin polymerization may help propel newly endocytosed vesicles into the spine cytosol where the activity or local concentration of uncoating proteins such as Synaptojanin is potentially higher.…”

Eph/ephrin molecules—a hub for signaling and endocytosis

“…While synaptic plasticity remains incompletely understood, important roles have been attributed to the modulation of the axon terminal and the function of neurotransmitter receptors. Synaptojanin 1, a polyphosphoinositide phosphatase, controls the internalization of postsynaptic AMPA receptor (Gong and De Camilli 2008), a process that has been linked to Eph/ephrin signaling (Fig. 2B).…”