Initiation, labile, and stabilization phases of experience-dependent plasticity at neocortical synapses.
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.
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ABSTRACT: Age-related molecular changes in the synapse can cause plasticity decline. We found an impairment of experience-dependent cortical plasticity is induced by short lasting sensory conditioning in aged mice. However, extending the training procedure from 3 to 7 days triggered plasticity in the aged cortex of the same range as in young mice. Additionally, GABAergic markers (GABA, GAD67, VGAT) in young and aged groups that showed the plastic changes were upregulated. This effect was absent in the aged group with impaired plasticity, while the expression of Vglut1 increased in all trained groups. This may reflect the inefficiency of inhibitory mechanisms in the aging brain used to control increased excitation after training and to shape proper signal to noise ratio, which is essential for appropriate stimuli processing. HPLC analysis showed that the glutamate/GABA ratio was significantly reduced in aged animals due to a significant decrease in glutamate level. We also observed a decreased expression of several presynaptic markers involved in excitatory (vesicular glutamate transporter-vglut2) and inhibitory (glutamic acid decarboxylase-GAD67, vesicular GABA transporter VGAT) transmission in the aged barrel cortex. These changes may weaken the plasticity potential of neurons and impede the experience-dependent reorganization of cortical connections. We suggest that the imbalance toward inhibition resulting from a decrease of glutamate content in the aging cerebral cortex, together with GABAergic system ineffectiveness in upregulating GABA level after sensory training, contributes to the impairment of learning-dependent cortical plasticity.Brain Structure and Function 03/2014; · 7.84 Impact Factor
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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. 01/2014; 8:153.
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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 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 boutonsLearning & memory (Cold Spring Harbor, N.Y.) 12/2014; · 4.08 Impact Factor