Molecular mechanisms of homeostatic synaptic downscaling

Abstract

Homeostatic synaptic downscaling is a negative feedback response to chronic elevated network activity to reduce the firing rate of neurons. This form of synaptic plasticity decreases the strength of individual synapses to the same proportion, or in a multiplicative manner. Because of this, synaptic downscaling has been hypothesized to counter the potential run-away excitation due to Hebbian type of long term potentiation (LTP), while preserving relative synaptic weight encoded in individual synapses and thus memory information. In this article, we will review the current knowledge on the signaling and molecular mechanisms of synaptic downscaling. Specifically, we focus on three general areas. First the functional roles of several immediate early genes such as Plk2, Homer1a, Arc and Narp are discussed. Secondly, we examine the current knowledge on the regulation of synaptic protein levels by ubiquitination and transcriptional repression in synaptic downscaling. Thirdly, we review the dynamics of signaling molecules such as kinases and phosphatases critical for synaptic downscaling, and their regulation of synaptic scaffolding proteins. Finally we briefly discuss the heterogeneity of homeostatic synaptic downscaling mechanisms. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

Activity-dependent PI(3,5)P 2 synthesis controls AMPA receptor trafficking during synaptic depression

“…This unidirectional role is consistent with a growing literature suggesting that distinct mechanisms underlie homeostatic synaptic strengthening and weakening (reviewed in refs. 53,58). Candidate pathways that may regulate PIKfyve or may be regulated by PIKfyve are mechanisms known to be important for homeostatic synaptic weakening (reviewed in refs.…”

“…Candidate pathways that may regulate PIKfyve or may be regulated by PIKfyve are mechanisms known to be important for homeostatic synaptic weakening (reviewed in refs. 53,58,87). These include PSD-95, Polo-like kinase 2 (Plk2), cyclin-dependent kinase 5 (CDK5), and L-type voltage-gated calcium channels.…”

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

“…These results could suggest the potential for a non-symmetric up-and downregulation, like that observed for LTP and LTD, where potentiation can occur more reliably and quickly [46]. As for experimental evidence for homeostatic downregulation, work in cortical cultures indicates that it is possible [5,20], but approaches for extended increases in activity in vivo remain elusive. The difficulty of maintaining heightened activity in vivo for extended periods of time, may speak to the existence of a fast downregulating homeostatic mechanism that has yet to be experimentally observed.…”

“…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. Numerous molecular mechanisms have been implicated in mediating synaptic scaling, including TNF-alpha [15][16][17], which may be regulated via astrocytic activity and N-methyl-D-aspartate (NMDA) receptor expression [18], retinoic acid [19], among many others (for a review, see [20,21]). Increases in TNF-alpha have been reported to increase and decrease the density of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and gamma aminobutyric acid-A (GABA A ) receptors, respectively, in the plasma membrane [17].…”

D-aspartate dysregulation in Ddo−/− mice modulates phencyclidine-induced gene expression changes of postsynaptic density molecules in cortex and striatum

“…Indeed, it has been observed that the induction of Homer1a triggers mGluR agonist-independent activity (Ango et al, 2001) and redirects intracellular signaling towards effectors different from those activated by Homer1b/c (Kammermeier and Worley, 2007). Since Homer1a has been described to play a role in synaptic downscaling (Hu et al, 2010;Siddoway et al, 2014) by promoting the hyperpolarization and reducing the activation of the postsynaptic neuron (Errico et al, 2014;Minami et al, 2003;Sylantyev et al, 2013), the reduction of its expression that we observed may represent one of the molecular mechanisms underpinning the elevated glutamatergic tone that has been reported in Ddo −/− mice as a consequence of the persistent elevated D-aspartate levels (Errico et al, 2015).…”