Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Abstract

Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.P roper development of neuronal circuits, as well as efficient information storage during learning and memory, are thought to depend upon the presence of homeostatic mechanisms that stabilize neuronal excitability (1-3). One such mechanism is synaptic scaling, which compensates for perturbations in average firing by scaling up or down the postsynaptic strength of all of a neuron's excitatory synapses (4). Synaptic scaling is a cell-autonomous process in which neurons detect changes in their own firing through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of AMPA receptors (AMPAR) at synaptic sites and thus increase or decrease synaptic strength (4-6). Despite great recent interest, the AMPA receptor-trafficking events that underlie synaptic scaling remain largely obscure. Defects in synaptic scaling have been postulated to contribute to disorders as diverse as Alzheimer's disease (7) and epilepsy (8), so illuminating the underlying AMPAR trafficking steps could shed light into the genesis of a wide range of neurological disorders.Most neocortical AMPAR are heteromeric receptors composed of both GluA1 and GluA2 subunits, which have unique phosphorylation sites and interact with distinct trafficking proteins (9). During synaptic scaling up in response to action potential blockade, synaptic strength is increased through enhanced synaptic accumulation of GluA1 and GluA2-containing AMPAR (5, 10-13) and requires the C-terminal domain of the GluA2 subunit (12), but which subunit-specific interactions underlie synaptic scaling remain controversial (12,14). Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate recepto...

Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions

“…Many studies have confirmed this original result in vitro [6], as well as ex vivo in acute slices prepared from both juvenile and adult animals that had previously undergone in vivo deprivation [7][8][9][10][11][12][13][14]. Synaptic scaling does have layer-specific properties in cortex, where scaling in layer 4 is limited to early development [7], but layer 5 [12,15] and layer 2/3 [10] can scale throughout adulthood.…”

Nascent Proteome Remodeling following Homeostatic Scaling at Hippocampal Synapses

“…Several groups have postulated that fluctuations in intracellular Ca 2+ levels initially “sense” changes in activity (Ibata et al., 2008, Thiagarajan et al., 2005) that may be read out by changes in the activation of CaMKIV resulting in changes in gene expression (Ibata et al., 2008). In addition, the expression of scaling up is mediated by the accumulation of GluR2-containing receptors (Gainey et al., 2009, Gainey et al., 2015), likely driven by alterations with the glutamate receptor-interacting protein-1, GRIP-1 (Gainey et al., 2015), and protein-interacting-with C Kinase 1, PICK1 (Anggono et al., 2011). Other molecules implicated in various aspects of synaptic scaling include the neurotrophin brain-derived neurotrophic factor (BDNF) (Rutherford et al., 1998), the immediate early gene Arc (Shepherd et al., 2006), the cytokine TNFα (Steinmetz and Turrigiano, 2010, Stellwagen and Malenka, 2006), the immune molecule MHC1 (Goddard et al., 2007), β3 integrins (Cingolani et al., 2008), and the scaffold proteins PSD-95 and PSD-93 (Sun and Turrigiano, 2011).…”

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).…”