GRIP1 is required for homeostatic regulation of AMPAR trafficking

Abstract

Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms underlying the homeostatic regulation of AMPARs remain elusive. Here, we show that the expression of GRIP1, a multi-PDZ (postsynaptic density 95/discs large/zona occludens) domain AMPAR-binding protein, is bidirectionally altered by neuronal activity. Furthermore, we observe a subcellular redistribution of GRIP1 and a change in the binding of GRIP1 to GluA2 during synaptic scaling. Using a combination of biochemical, genetic, and electrophysiological methods, we find that loss of GRIP1 blocks the accumulation of surface AMPARs and the scaling up of synaptic strength that occur in response to chronic activity blockade. Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced synaptic scaling.synaptic scaling | postsynaptic density | glutamate receptor | PDZ domain

Upregulation of μ3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway

“…4D,E) but not sufficient for the regulated recruitment of AMPAR to the synaptic membrane during synaptic scaling, suggesting that an additional trafficking step is required to bring internal AMPAR to the synaptic membrane. GRIP1 accumulates at sites of exocytosis as well as at synapses, and is essential to recruit AMPAR to synapses during synaptic scaling up (Gainey et al, 2015; Tan et al, 2015). To determine whether the μ3A-dependent trafficking of GluA2 into the recycling pathway enhances the ability of GRIP1 to recruit GluA2 to the membrane, we compared surface levels of endogenous GluA2 after OE of μ3A alone, GRIP1 alone, or μ3A + GRIP1 (Fig.…”

“…The RE compartment has been shown to be critical for supplying AMPAR during LTP (Hanley, 2010; Park et al, 2004), but whether they also supply AMPAR for synaptic scaling has been less clear (Gainey et al, 2015, Tan et al, 2015). Interestingly, although an increase in μ3A is necessary for scaling, and is necessary and sufficient to drive AMPAR to RE, it is not sufficient to increase mEPSC amplitude.…”

“…This suggests that, once AMPAR are rerouted into the recycling pathway by μ3A, they must still be recruited to the synaptic membrane in a second activity-dependent trafficking step. The GluA2-interacting protein GRIP1 plays a critical role in recruiting AMPAR from internal endosomal compartments to the synaptic membrane during synaptic scaling (Gainey et al, 2015; Tan et al, 2015). Here we show that when μ3A and GRIP1 are OE together, they can act synergistically to enhance surface AMPAR accumulation, providing direct experimental support for a two-step trafficking model in which μ3A recruits AMPAR into the recycling pathway, where they can then be recruited to and stabilized by GRIP1 at the synaptic membrane (Fig.…”

Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons

“…For example, brain-derived neurotrophic factor (BDNF) is important for homeostatic upscaling; BDNF depletion resembles TTX-induced mEPSC amplitude upscaling. Additional factors that mediate upscaling include tumor necrosis factor alpha (TNFα), the C-kinase 1-interacting protein PICK1 and the glutamate receptor interacting protein GRIP1, and the immediate early gene Arc (Gainey et al, 2015; Tan et al, 2015; Turrigiano, 2012; Wang et al, 2012a). Further, homer1a and Eph4A receptor tyrosine kinase are important for neuronal activity-induced synaptic downscaling (Turrigiano, 2012).…”

Sensory Input-Dependent Changes in Glutamatergic Neurotransmission- Related Genes and Proteins in the Adult Rat Trigeminal Ganglion

“…The disruption of GRIP1-GLUR2 interaction is needed for LTD (Kim et al, 2001). Moreover, it has been recently shown that the total amount of GRIP1 and its intracellular distribution is activity- dependent: during neuronal inactivity GRIP1 is reduced, which stabilizes AMPA receptors in the membrane, while under conditions of forced neuronal activity, GRIP1 increases, and removes AMPA from synapses toward the cytoplasm (Tan et al, 2015). PICK1 role in AMPA receptor trafficking is essential for NMDAR-dependent LTD, by its Ca 2+ dependent capacity to retain AMPA receptors that have been internalized in the first stages of LTD (Terashima et al, 2008; Citri et al, 2010).…”