Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex

Clem, Roger L.; Celikel, Tansu; Barth, Alison L.

doi:10.1126/science.1143808

Cited by 148 publications

(199 citation statements)

References 27 publications

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“…Likewise, the synaptic strengthening that occurs in the spared barrel column when all but one whisker are removed hinders subsequent generation of NMDA receptor-dependent long-term potentiation at layer IV to layer II-III synapses in mouse brain slices (Clem et al, 2008). Nevertheless, further plasticity remains possible at these synapses through metabotropic glutamate receptors (Clem et al, 2008), raising the possibility that several distinct plasticity mechanisms interact in shaping cortical processing as a function of sensory experience.…”

Section: Discussionmentioning

confidence: 99%

“…If plasticity were induced by this rhythmic input, it should interfere with the effects of subsequent passive 8 Hz whisker stimulation. Similar approaches have recently been used to establish a link between behavioral training or manipulation of sensory experience and neocortical long-term potentiation (Rioult-Pedotti et al, 2000;Clem et al, 2008).…”

Section: Environmental Enrichment Occludes 8 Hz Whisker Stimulation-imentioning

confidence: 99%

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Long-Term Plasticity in Mouse Sensorimotor Circuits after Rhythmic Whisker Stimulation

et al. 2009

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Mice actively explore their environment by rhythmically sweeping their whiskers. As a consequence, neuronal activity in somatosensory pathways is modulated by the frequency of whisker movement. The potential role of rhythmic neuronal activity for the integration and consolidation of sensory signals, however, remains unexplored. Here, we show that a brief period of rhythmic whisker stimulation in anesthetized mice resulted in a frequency-specific long-lasting increase in the amplitude of somatosensory-evoked potentials in the contralateral primary somatosensory (barrel) cortex. Mapping of evoked potentials and intracortical recordings revealed that, in addition to potentiation in layers IV and II/III of the barrel cortex, rhythmic whisker stimulation induced a decrease of somatosensory-evoked responses in the supragranular layers of the motor cortex. To assess whether rhythmic sensory input-based plasticity might arise in natural settings, we exposed mice to environmental enrichment. We found that it resulted in somatosensory-evoked responses of increased amplitude, highlighting the influence of previous sensory experience in shaping sensory responses. Importantly, environmental enrichment-induced plasticity occluded further potentiation by rhythmic stimulation, indicating that both phenomena share common mechanisms. Overall, our results suggest that natural, rhythmic patterns of whisker activity can modify the cerebral processing of sensory information, providing a possible mechanism for learning during sensory perception.

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Section: Discussionmentioning

confidence: 99%

Section: Environmental Enrichment Occludes 8 Hz Whisker Stimulation-imentioning

confidence: 99%

Long-Term Plasticity in Mouse Sensorimotor Circuits after Rhythmic Whisker Stimulation

et al. 2009

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“…Several studies demonstrate key roles for mGluRs in regulating experience-dependent circuit plasticity in response to visual experience (40,41), fear conditioning (42), and somatosensory experience (9,43). Moreover, recent studies of mGluR-dependent synaptic plasticity have led to the discovery of novel cellular and molecular mechanisms with implications for diseases such as Fragile X syndrome and Alzheimer's disease (26,44,45).…”

Section: Discussionmentioning

confidence: 99%

Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening

Hill

Zito

2012

Proc. Natl. Acad. Sci. U.S.A.

147

149

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Refinement of neural circuits in the mammalian cerebral cortex shapes brain function during development and in the adult. However, the signaling mechanisms underlying the synapse-specific shrinkage and loss of spiny synapses when neural circuits are remodeled remain poorly defined. Here, we show that low-frequency glutamatergic activity at individual dendritic spines leads to synapse-specific synaptic weakening and spine shrinkage on CA1 neurons in the hippocampus. We found that shrinkage of individual spines in response to lowfrequency glutamate uncaging is saturable, reversible, and requires NMDA receptor activation. Notably, shrinkage of large spines additionally requires signaling through metabotropic glutamate receptors (mGluRs) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs), supported by higher levels of mGluR signaling activity in large spines. Our results support a model in which signaling through both NMDA receptors and mGluRs is required to drive activity-dependent synaptic weakening and spine shrinkage at large, mature dendritic spines when neural circuits undergo experience-dependent modification.two-photon microscopy | long-term depression | synaptic plasticity | spine dynamics S tructural plasticity of neurons, such as the growth and retraction of dendritic spines, is thought to contribute to the experience-dependent changes in brain circuitry that mediate learning and memory (1, 2). In particular, the destabilization and loss of spiny synapses plays a critical role in the refinement of neural circuits during development and during learning. Indeed, spine elimination occurs more frequently than does spine formation in young rodents between the first and the third month of age (3-5), a period when experience-dependent refinement of neural circuitry is in its peak. Furthermore, several in vivo studies demonstrate that manipulations leading to experience-dependent circuit plasticity also increase the rate of spine shrinkage and loss (6-9). However, it remains unclear how neural activity drives the selective shrinkage and loss of individual dendritic spines in response to sensory experience.Dendritic spines occur in a wide variety of shapes and sizes (10, 11), and their stability is strongly correlated with spine size (3, 12, 13). Small spines are in general more motile and thought to serve as substrates for plasticity, or "learning" spines; large spines are more stable and thought to serve as components of functioning neural circuits, or "memory" spines (12,14). It is the selective shrinkage and loss of individual circuit-incorporated, persistent spines that underlies experience-dependent circuit refinement (6, 9, 15). Thus, experience-dependent circuit remodeling requires an activity-dependent mechanism that selectively induces shrinkage and retraction of those specific individual dendritic spines that are no longer useful for circuit function.Previous studies have established that low-frequency glutamatergic stimulation (LFS), which causes long-term depression (LTD) of synaptic transmission in...

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“…On the other hand, reduced activity of either of these two receptors causes cognitive deficits in this paradigm (Boess et al, 2007;Curzon et al, 2006;Morris, 2006;Wallace et al, 2011). More generally, treatment of experimental animals with glutamate receptor antagonists impairs performance in a variety of cognitive tasks (Ahlander et al, 1999;Hauber and Schmidt, 1989;Karasawa et al, 2008;Venable and Kelly, 1990), whereas endogenous or exogenous glutamate receptor agonists promote cognitive performance (Clem et al, 2008;Lynch et al, 2008;Singer et al, 2010). Although definitive confirmation will require further experimentation and additional brain areas may well be involved (Jo et al, 2007), the present findings suggest that the cognitive impairment caused by elevated KYNA was likely related to reductions in extracellular glutamate in the hippocampus, and that the cognition-enhancing effects of ESBA were the result of elevated extracellular glutamate.…”

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex

Cited by 148 publications

References 27 publications

Long-Term Plasticity in Mouse Sensorimotor Circuits after Rhythmic Whisker Stimulation

Long-Term Plasticity in Mouse Sensorimotor Circuits after Rhythmic Whisker Stimulation

Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

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