NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P2 Is Essential for AMPA Receptor Endocytosis during LTD

Unoki, Takamitsu; Matsuda, Shinji; Kakegawa, Wataru; Van, Ngo Thai Bich; Kohda, Kazuhisa; Suzuki, Atsushi; Funakoshi, Yuji; Hasegawa, Hiroshi; Yuzaki, Michisuke; Kanaho, Yasunori

doi:10.1016/j.neuron.2011.09.034

Cited by 63 publications

(61 citation statements)

References 72 publications

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“…In agreement with previous reports (30,32), we found that the surface HA-GluR2 decreased rapidly following NMDA stimulation in WT but not in Prex1 −/− neurons ( Fig. 7 C and D).…”

Section: Significancesupporting

confidence: 93%

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Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphatedependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateralcornus ammonis region 1 (SC-CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition defici...

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“…In agreement with previous reports (30,32), we found that the surface HA-GluR2 decreased rapidly following NMDA stimulation in WT but not in Prex1 −/− neurons ( Fig. 7 C and D).…”

Section: Significancesupporting

confidence: 93%

“…PP1 is a vital factor required for CA1 NMDAR-dependent LTD and AMPAR endocytosis (31,32). Previous findings have suggested that PP1α, the catalytic subunit of PP1, binds to the RVxF motif in the C-terminal IP4P domain of P-Rex1 and dephosphorylates adjacent serine residues in nonneuronal cells.…”

Section: Significancementioning

confidence: 99%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The AMPA receptor (AMPAR) complex containing dephosphorylated STG may be trapped in the endocytic zone as the complex undergoes lateral diffusion, when the negatively charged lipid PIP 2 , which is enriched at the endocytic zone, binds to dephosphorylated STG 13 . Calcineurin also activates production of PIP 2 at the endocytic zone as shown by the dotted arrow 26 . As AP-2 also binds PIP 2 and accumulates at the endocytic zone, the AMPAR complex then enters the clathrin-mediated endocytosis process as a result of the interaction between STG and AP-2.…”

Section: Discussionmentioning

confidence: 99%

Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression

et al. 2013

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Long-term depression (LTD) underlies learning and memory in various brain regions. Although postsynaptic AMPA receptor trafficking mediates LTD, its underlying molecular mechanisms remain largely unclear. Here we show that stargazin, a transmembrane AMPA receptor regulatory protein, forms a ternary complex with adaptor proteins AP-2 and AP-3A in hippocampal neurons, depending on its phosphorylation state. Inhibiting the stargazin-AP-2 interaction disrupts NMDA-induced AMPA receptor endocytosis, and inhibiting that of stargazin-AP-3A abrogates the late endosomal/lysosomal trafficking of AMPA receptors, thereby upregulating receptor recycling to the cell surface. Similarly, stargazin's interaction with AP-2 or AP-3A is necessary for low-frequency stimulus-evoked LTD in CA1 hippocampal neurons. Thus, stargazin has a crucial role in NMDA-dependent LTD by regulating two trafficking pathways of AMPA receptors-transport from the cell surface to early endosomes and from early endosomes to late endosomes/lysosomes-through its sequential binding to AP-2 and AP-3A.

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“…Considering the critical function of Arf6 in the activation of the phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme phosphatidylinositol 4-phosphate 5-kinase (PIP5K) 26 , Arf6 could control FGF-2 secretion through PIP5K activation. Of three PIP5K isozymes, PIP5Kg is specifically expressed in neurons 27 and its activation is dependent on its phosphorylation/ dephosphorylation state: the phosphorylated form of PIP5Kg present in resting cells is dephosphorylated on cellular stimulation to interact with AP-2 and talin, which then activate it 28,29 . However, it is unlikely that PIP5Kg is involved in Arf6-dependent FGF-2 secretion, as its phosphorylation status was not changed by neuronal Arf6 ablation ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

et al. 2014

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The small G protein ADP-ribosylation factor 6 (Arf6) plays important roles in a wide variety of membrane dynamics-based cellular events such as neurite outgrowth and spine formation in vitro. However, little is known about physiological function of Arf6 in vivo. Here we generate conditional knockout mice lacking Arf6 in neurons, oligodendrocytes, or both cell lineages, and unexpectedly find that Arf6 expression in neurons, but not in oligodendrocytes, is crucial for oligodendrocyte myelination in the hippocampal fimbria and the corpus callosum during development, and that this is through the regulation of secretion of fibroblast growth factor-2, a guidance factor for migration of oligodendrocyte precursor cells (OPCs). These results suggest that Arf6 in neurons plays an important role in OPC migration through regulation of FGF-2 secretion during neuronal development.

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NMDA Receptor-Mediated PIP5K Activation to Produce PI(4,5)P2 Is Essential for AMPA Receptor Endocytosis during LTD

Cited by 63 publications

References 72 publications

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression

Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

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