Synaptic lability after experience-dependent plasticity is not mediated by calcium-permeable AMPARs

Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh PA, USA.
Frontiers in Molecular Neuroscience (Impact Factor: 4.08). 02/2012; 5:15. DOI: 10.3389/fnmol.2012.00015
Source: PubMed

ABSTRACT Activity- or experience-dependent plasticity has been associated with the trafficking of calcium-permeable AMPARs (CP-AMPARs) in a number of experimental systems. In some cases it has been shown that CP-AMPARs are only transiently present and can be removed in an activity-dependent manner. Here we test the hypothesis that the presence of CP-AMPARs confers instability onto recently potentiated synapses. Previously we have shown that altered sensory input (single-whisker experience; SWE) strengthens layer 4-2/3 excitatory synapses in mouse primary somatosensory cortex, in part by the trafficking of CP-AMPARs. Both in vivo and in vitro, this potentiation is labile, and can be depressed by NMDAR-activation. In the present study, the role of CP-AMPARs in conferring this synaptic instability after in vivo potentiation was evaluated. We develop an assay to depress the strength of individual layer 4-2/3 excitatory synapses after SWE, using a strontium (Sr++)-replaced ACSF solution (Sr-depression). This method allows disambiguation of changes in quantal amplitude (a post-synaptic measure) from changes in event frequency (typically a presynaptic phenomenon). Presynaptic stimulation paired with postsynaptic depolarization in Sr++ lead to a rapid and significant reduction in EPSC amplitude with no change in event frequency. Sr-depression at recently potentiated synapses required NMDARs, but could still occur when CP-AMPARs were not present. As a further dissociation between the presence of CP-AMPARs and Sr-depression, CP-AMPARs could be detected in some cells from control, whisker intact animals, although Sr-depression was never observed. Taken together, our findings suggest that CP-AMPARs are neither sufficient nor necessary for experience-dependent synaptic plasticity in somatosensory neocortex.

Download full-text


Available from: Alison L Barth, Aug 21, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alteration of sensory input can change the strength of neocortical synapses. Selective activation of a subset of whiskers is sufficient to potentiate layer 4-layer 2/3 excitatory synapses in the mouse somatosensory (barrel) cortex, a process that is NMDAR dependent. By analyzing the time course of sensory-induced synaptic change, we have identified three distinct phases for synaptic strengthening in vivo. After an early, NMDAR-dependent phase where selective whisker activation is rapidly translated into increased synaptic strength, we identify a second phase where this potentiation is profoundly reduced by an input-specific, NMDAR-dependent depression. This labile phase is transient, lasting only a few hours, and may require ongoing sensory input for synaptic weakening. Residual synaptic strength is maintained in a third phase, the stabilization phase, which requires mGluR5 signaling. Identification of these three phases will facilitate a molecular dissection of the pathways that regulate synaptic lability and stabilization, and suggest potential approaches to modulate learning.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2013; 33(19):8483-93. DOI:10.1523/JNEUROSCI.3575-12.2013 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs) to the post-synaptic membrane, and is developmentally regulated. How enhanced sensory experience can alter presynaptic release properties in the developing neocortex has not been investigated. Using paired-pulse stimulation at layer 4-2/3 synapses in acute brain slices, we found that presynaptic release probability progressively increases in the spared-whisker barrel column over the first 24 h of SRE. Enhanced release probability can be at least partly attributed to presynaptic NMDA receptors (NMDARs). We find that the influence of presynaptic NMDARs in enhancing EPSC amplitude markedly increases during SRE. This occurs at the same time when recently potentiated synapses become highly susceptible to a NMDAR-dependent form of synaptic depression, during the labile phase of plasticity. Thus, these data show that augmented sensory stimulation can enhance release probability at layer 4-2/3 synapses and enhance the function of presynaptic NMDARs. Because presynap-tic NMDARs have been linked to synaptic depression at layer 4-2/3 synapses, we propose that SRE-dependent up-regula-tion of presynaptic NMDARs is responsible for enhanced synaptic depression during the labile stage of plasticity. [Supplemental material is available for this article.] Sensory experience can enhance the spike output of neocortical neurons, a phenomenon that has been widely investigated at a cellular and molecular level across multiple brain areas. Experi-ence-dependent potentiation of neuronal responses has been well characterized in somatosensory cortex (S1), where synaptic potentiation, the addition of new synaptic contacts, and a reduc-tion in local inhibition all play a role in transforming the output of neural circuits (Finnerty et al. 1999; Knott et al. 2002; Barth et al. 2004; Clem and Barth 2006; Jiao et al. 2006; Cheetham et al. 2007; Wen and Barth 2011; Jacob et al. 2012). During post-natal development, experience-dependent plasticity is enhanced, and there has been great interest in understanding the cellular and molecular mechanisms that regulate this phenomenon in order to facilitate learning in other training paradigms as well as to restore plasticity in adults (Feldman et al. 1998; Pizzorusso et al. 2002; Hensch 2005; Di Cristo et al. 2007; Morishita et al. 2010; Gu et al. 2013; Kuhlman et al. 2013). At layer 4-2/3 synapses of primary somatosensory (barrel) cortex in mice, experience-dependent glutamatergic synaptic strengthening is associated with the trafficking of post-synaptic AMPARs. In contrast to activity-dependent changes in post-synaptic measures of synaptic strength in primary sensory cortex, presynaptic changes have been less well characterized. Although sensory deprivation can decrease release probability at glutama-tergic synapses in neocortical areas representing the deprived inputs (Bender et al. 2006a), it is unknown whether selective sen-sory stimulation can enhance release. Indeed, it is conceivable that post-synaptic potentiation is accompanied by a reduction in release probability, as a homeostatic adjustment to the in-creased activity of this pathway (Turrigiano et al. 1998). Here we sought to investigate whether whisker-driven activ-ity in barrel cortex could alter presynaptic release properties at lay-er 4-2/3 synapses. We focused on SRE-driven plasticity at the end of the second post-natal week, since the timecourse and receptor subtypes required for post-synaptic changes in this experimental paradigm are well characterized. During SRE, layer 4-2/3 synapses in the whisker-spared barrel columns show a rapid NMDAR-de-pendent increase in strength over the first 12 h, nearly doubling in amplitude (Wen et al. 2013). Potentiated layer 4-2/3 synapses then undergo an input-dependent reduction in synaptic strength also linked to NMDAR activation during the labile phase, that lasts 12 h before changes become stabilized (Wen et al. 2013). The transition from NMDAR-dependent potentiation to NMDAR-dependent depression during SRE is a form of synaptic metaplasticity that can be observed both in vivo and in vitro (Clem et al. 2008). The mechanistic basis for this SRE-dependent change in NMDAR function remains obscure. Because NMDARs can occur both pre-and post-synaptically at layer 4-2/3 synapses, modification at both sites is possible (Corlew et al. 2008). Presynaptic NMDARs have been anatomically observed at neocortical synapses, where they are localized to axonal boutons
    Learning & memory (Cold Spring Harbor, N.Y.) 12/2014; 22(1). DOI:10.1101/lm.035741.114 · 4.38 Impact Factor