Initiation, Labile, and Stabilization Phases of Experience-Dependent Plasticity at Neocortical Synapses
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.
Available from: Puja Parekh
- "Layer 4-2/3 EPSCs were evoked using extracellular stimulation in the center of a layer 4 barrel (Fig. 1C), and paired stimuli were delivered at 30 Hz (Fig. 1D). Previous studies have shown that this SRE manipulation is sufficient to increase the quantal amplitude of layer 4-2/3 EPSCs (Clem and Barth 2006; Clem et al. 2010; Wen et al. 2013). In the control, whisker-intact animals, mean PPR is on average modestly depressing (Fig. 1E; 0.92 + 0.06; n ¼ 22 cells and 14 mice), consistent with prior studies in young animals (Reyes et al. 1998; Rozov et al. 2001; Bender et al. 2006a,b; Brasier and Feldman 2008). "
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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 presynaptic NMDARs have been linked to synaptic depression at layer 4-2/3 synapses, we propose that SRE-dependent up-regulation of presynaptic NMDARs is responsible for enhanced synaptic depression during the labile stage of plasticity.
Learning & memory (Cold Spring Harbor, N.Y.) 12/2014; 22(1). DOI:10.1101/lm.035741.114 · 3.66 Impact Factor
Available from: Kally C O'Reilly
- "This synaptic restructuring promotes neural coordination in CA1 in support of cognitive control and flexibility. In addition to synaptic plasticity mechanisms, cognitive training may alter neural circuit and synaptic network function by changing the expression of dendritic spine structure (Yang et al., 2009) and/or structural proteins (Gray et al., 2006; Clem et al., 2008; Wen et al., 2013). In fact, we have observed that place avoidance training in adolescence decreased parvalbumin expression in mPFC interneurons (Lee et al., 2012). "
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ABSTRACT: Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry.
Frontiers in Neuroscience 06/2014; 8(8):153. DOI:10.3389/fnins.2014.00153 · 3.66 Impact Factor
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ABSTRACT: Fragile X syndrome (FXS) is the most common inherited neurodevelopmental disorder with intellectual disability. Here, we show that the expression of tissue plasminogen activator (tPA) is increased in glial cells differentiated from neural progenitors of Fmr1 knock-out mice, a mouse model for FXS, and that tPA is involved in the altered migration and differentiation of these progenitors lacking FMR1 protein (FMRP). When tPA function is blocked with an antibody, enhanced migration of doublecortin-immunoreactive neurons in 1 d differentiated FMRP-deficient neurospheres is normalized. In time-lapse imaging, blocking the tPA function promotes early glial differentiation and reduces the velocity of nuclear movement of FMRP-deficient radial glia. In addition, we show that enhanced intracellular Ca(2+) responses to depolarization with potassium are prevented by the treatment with the tPA-neutralizing antibody in FMRP-deficient cells during early neural progenitor differentiation. Alterations of the tPA expression in the embryonic, postnatal, and adult brain of Fmr1 knock-out mice suggest an important role for tPA in the abnormal neuronal differentiation and plasticity in FXS. Altogether, the results indicate that tPA may prove to be an interesting potential target for pharmacological intervention in FXS.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2014; 34(5):1916-23. DOI:10.1523/JNEUROSCI.3753-13.2014 · 6.34 Impact Factor
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