Non-scaling regulation of AMPA receptors in homeostatic synaptic plasticity
Graphical abstract
Introduction
In neurons, homeostatic plasticity serves to maintain a stable firing rate of action potentials. This can be achieved through adjustments in the strength of synaptic activity, neuronal excitability, neural cells connectivity, or the balance of excitation and inhibition (Turrigiano 2008, 2011; Pozo and Goda, 2010; Vitureira et al., 2012; Fernandes and Carvalho, 2016; Matsubara and Uehara, 2016). Among these possibilities, regulation of synaptic strength has been the most extensively studied and is believed to be the most crucial measure in homeostatic regulation, also known as homeostatic synaptic plasticity (HSP) (Turrigiano et al., 1998; Davis and Bezprozvanny, 2001; Davis, 2006; Shepherd et al., 2006; Stellwagen and Malenka, 2006; Turrigiano, 2008; Hou et al 2011, 2015). In addition to its roles in maintaining normal physiological brain functions, the contributions of HSP to neurological and psychiatric diseases, such as Alzheimer's disease and autism, have also been gradually revealed in recent years (Pratt et al., 2011; Blackman et al., 2012; Gilbert et al., 2016; Jewett et al., 2018; Lee et al., 2018; Styr and Slutsky, 2018).
At the cellular level, inactivity-dependent homeostatic plasticity causes a simultaneous up-regulation of AMPAR at all synapses (Stellwagen and Malenka, 2006; Sutton et al., 2006; Aoto et al., 2008; Hou et al., 2008; Ibata et al., 2008; Pozo and Goda, 2010; Vitureira et al., 2012; Wang et al., 2012; Soares et al., 2013; Diering and Huganir, 2018). It has been proposed that during the expression of homeostatic regulation, the amount of AMPAR added to each synapse is not by chance; rather, the response at individual synapse follows a common rule. In previous studies of HSP, the amplitudes of mEPSCs were often analyzed by cumulative plotting that ranks the miniature synaptic currents from the smallest to the largest (Turrigiano et al., 1998; Wierenga et al., 2005; Stellwagen and Malenka, 2006; Turrigiano, 2008). The multiplicative pattern of the cumulative curves is thought to be a result from proportional increases in transmission strength of all synapses, namely, synaptic scaling. Synaptic scaling is considered an important cellular mechanism by which the relative strength of individual synaptic input can be maintained following homeostatic plasticity. It has been hypothesized that synaptic scaling of mEPSCs is due to the proportional addition of AMPAR to the entire synapse population of a neuron (Ibata et al., 2008; Pozo and Goda, 2010; Turrigiano, 2008). However, this hypothesis, though of fundamental significance, has not been validated by direct experimental evidence. We therefore directly examined AMPAR synaptic scaling in cultured neurons by a series of live-imaging experiments to compare changes of synaptic AMPAR amounts during HSP. To our surprise, we found that while AMPAR amount was increased in most synapses after neural activity deprivation, AMPAR accumulation did not show the expected pattern of scaling. Instead, among the synapse population, the extents of synaptic AMPAR increases showed a wide range of variation during HSP.
Section snippets
Live-imaging shows homeostatic up-regulation of synaptic AMPAR induced by neural activity deprivation
In order to analyze AMPAR accumulation at single synapse during HSP, we performed live-imaging on cultured hippocampal neurons expressing GFP-tagged (GFP-GluA1, GFP-GluA2) or pHluorin-tagged (pH-GluA1) AMPAR subunits, respectively. Two-wk-old hippocampal neurons were transfected for 3 days to express the target protein before experiments (Fig. 1A). Immunostaining of a synaptic marker PSD-95 indicated that the GFP-GluA1/2 or pH-GluA1 was successfully expressed and localized at the synaptic sites
Discussion
By utilizing high-resolution live-imaging of GFP-tagged AMPAR subunits, we analyzed the homeostatic up-regulation of AMPARs at individual synapses. Most importantly, we found that during HSP, changes in AMPAR synaptic accumulation, while showing up-regulation in most synapses, did not scale up uniformly among the synapse population. Under activity deprivation by APV + TTX treatment, individual AMPAR puncta at the synapses of a neuron show a wide range of changes, including down-regulation,
Acknowledgements
We would like to thank Dr. Margaret Hastings for comments on the manuscript and the Man Lab members for helpful discussion. This work was supported by NIH grant R01 MH079407 (H.Y.M.) and International Fulbright Sci & Tech Outstanding Student Award (G.W.). The authors declare no conflicts of financial interests.
References (37)
Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity
Neuron
(2008)- et al.
The AMPA receptor code of synaptic plasticity
Neuron
(2018) The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP
Neuron
(2011)Polarized secretory trafficking directs cargo for asymmetric dendrite growth and morphogenesis
Neuron
(2005)Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation
Neuron
(2011)Rapid synaptic scaling induced by changes in postsynaptic firing
Neuron
(2008)Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice
Neuropharmacology
(2018)- et al.
Unraveling mechanisms of homeostatic synaptic plasticity
Neuron
(2010) Arc/Arg 3.1 mediates homeostatic synaptic scaling of AMPA receptors
Neuron
(2006)Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis
Cell
(2006)
The self-tuning neuron: synaptic scaling of excitatory synapses
Cell
Homeostatic synaptic plasticity: from single synapses to neural circuits
Curr. Opin. Neurobiol.
Resveratrol up-regulates AMPA receptor expression via AMP-activated protein kinase-mediated protein translation
Neuropharmacology
Deprivation-induced homeostatic spine scaling in vivo is localized to dendritic branches that have undergone recent spine loss
Neuron
Arc-dependent synapse-specific homeostatic plasticity
Proc. Natl. Acad. Sci. U. S. A.
A critical and cell-autonomous role for MeCP2 in synaptic scaling up
J. Neurosci.
Homeostatic control of neural activity: from phenomenology to molecular design
Annu. Rev. Neurosci.
Maintaining the stability of neural function: a homeostatic hypothesis
Annu. Rev. Physiol.
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