Structural basis for the role of inhibition in facilitating adult brain plasticity

Chen, Jerry L.; Lin, Walter C.; Won, Jae Yon; So, Peter T. C.; Kubota, Yoshihiro; Nedivi, Elly

doi:10.1038/nn.2799

Cited by 199 publications

(240 citation statements)

References 49 publications

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“…One study reported an early loss of spines, thus reducing excitatory inputs onto a subpopulation of inhibitory interneurons (mainly neuropeptide Y-positive), and a subsequent loss of axonal boutons, thus reducing inhibitory output by the same interneurons upon sensory deprivation 98 . The second study reported a loss of excitatory inputs onto inhibitory neurons in layer 2/3 upon visual deprivation 99 . Together, the studies suggest that early structural plasticity in sensory-deprived cortex may lead to a diminished excitatory drive onto inhibitory interneurons, suggesting a possible structural basis for disinhibition and enhanced excitation.…”

Section: Inhibitory Circuit Rearrangementsmentioning

confidence: 97%

Structural plasticity upon learning: regulation and functions

2012

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The contributions of brain networks to information processing and learning and memory are classically interpreted within the framework of Hebbian plasticity and the notion that synaptic weights can be modified by specific patterns of activity. However, accumulating evidence over the past decade indicates that synaptic networks are also structurally plastic, and that connectivity is remodelled throughout life, through mechanisms of synapse formation, stabilization and elimination 1. This has led to the concept of structural plasticity, which can encompass a variety of morphological changes that have functional consequences. These include on the one hand structural rearrangements at pre-existing synapses, and on the other hand the formation or loss of synapses, of neuronal processes that form synapses or of neurons. In this Review we focus on plasticity that involves gains and/or losses of synapses. Its key potential implication for learning and memory is to physically alter circuit connectivity, thus providing long-lasting memory traces that can be recruited at subsequent retrieval. Detecting this form of plasticity and relating it to its possible functions poses unique challenges, which are in part due to our still limited understanding of how structure relates to function in the nervous system.We review recent studies that relate the structural plasticity of neuronal circuits to behavioural learning and memory and discuss conceptual and mechanistic advances, as well as future challenges. The studies establish a number of strong links between specific behavioural learning processes and the assembly and loss of specific synapses. Further areas of substantial progress include molecular and cellular mechanisms that regulate synapse dynamics in response to alterations in synaptic activity, the specific spatial distribution of the syn aptic changes among identified neurons and dendrites and the relative roles of excitation and inhibition in regulating structural plasticity.The new findings provide exciting early vistas of how learning and memory may be implemented at the level of structural circuit plasticity. At the same time, they highlight major gaps in our understanding of plasticity regulation at the cellular, circuit and systems levels. Accordingly, achieving a better mechanistic understanding of learning and memory processes is likely to depend on the development of more effective techniques and models to investigate ensembles of identified synapses longitudinally, both functionally and structurally. Molecular mechanisms of synapse remodellingA remarkable feature of excitatory and inhibitory synapses is their high level of structural variability 2 and the fact that their morphologies and stabilities change over time 3 . This phenomenon is regulated by activity, and the size of spine heads correlates with synaptic strength 4 , presynaptic properties 5 and the long-term stability of the synapse 6 . The morphological characteristics of synapses thus reveal important features of their function and stabilit...

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Section: Inhibitory Circuit Rearrangementsmentioning

confidence: 97%

Structural plasticity upon learning: regulation and functions

2012

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“…Circuit-specific defects in calcium buffer capacity in the Ag brain (3) may lead to increases in calcium levels, which in turn may lead to increased axonal bouton instability. In parallel, progressive hypofunctionality of inhibitory networks (47) could disrupt the balance between excitation and inhibition, leading to hyperexcitability and uncontrolled EPB plasticity in excitatory circuits (3,48).…”

Section: Increased Rates Of Change In Axonal Bouton Size and Cognitivementioning

confidence: 99%

Increased axonal bouton dynamics in the aging mouse cortex

Grillo

Song

Ruivo

et al. 2013

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

114

100

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Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for agerelated cognitive decline.neural circuits | ageing | structural plasticity | axon | in vivo imaging W hat are the cellular mechanisms that lead to age-related cognitive decline? There is significant evidence suggesting that synaptic impairment, rather than neuronal loss, may be the leading cause of cognitive deterioration (1-3). However, the mechanisms that underlie this synaptic impairment remain poorly understood.It is widely believed that learning deficits within the aging brain result from reduced synaptic density and plasticity (3). Most studies so far have focused on dendritic spines, the postsynaptic sites of excitatory synapses. Both the size and the number of dendritic spines are affected in pyramidal neurons of the aged (Ag) cortex and hippocampus (2-5). Interestingly, it is mainly thin spines, likely to be the main site of postsynaptic plasticity (6), that are reduced in numbers and display a larger spine head volume in cortical neurons of the Ag monkey (7) and in rat cortex (8). Much less is known about presynaptic deficits with aging. Synaptophysin (a synaptic vesicle component) labeling decreases (9), and treatments that rescue age-related cognitive decline lead to increased synaptophysin immunoreactivity and increased synaptic plasticity in the hippocampus (10). Overall these findings from different brain areas and species point to a reduction of the number, size, and plasticity of neuronal connections in the Ag brain. However, most studies to date h...

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“…A direct demonstration that GABAergic inhibition is a crucial brake limiting VC plasticity derives from the recent observation that a pharmacological reduction of inhibitory transmission effectively restores OD plasticity in adulthood (Harauzov et al, 2010). This is consistent with the fact that experimental paradigms such as dark exposure (He et al, 2006), environmental enrichment Sale et al, 2010), food restriction , long-term fluoxetine (FLX) administration (MayaVetencourt et al, 2008;Chen et al, 2011;Maya-Vetencourt et al, 2011), and exogenous IGF-I administration (Maya-Vetencourt et al, 2012), all promote plasticity late in life by reducing the intracortical inhibitory/excitatory (I/E) ratio. This has prompted the search for endogenous factors with the potential to enhance plasticity in adult life by modulating the intracortical I/E balance.…”

Section: Sensory Experience Triggers the Maturation Of Inhibitory Cirmentioning

confidence: 69%

“…In light of these findings, one can speculate that the beneficial effects exerted by these treatments could be exploited for clinical application. Since deterioration in functional plasticity contributes to the pathogenesis of several brain diseases, environmental enrichment , food restriction , brief dark exposure (He et al, 2006), long-term fluoxetine treatment (Maya-Vetencourt et al, 2008;Chen et al, 2011;Maya-Vetencourt et al, 2011) and exogenous IGF-I administration (MayaVetencourt et al, 2012), all of which reactivate adult brain plasticity, arise as potential therapeutic strategies for pathological conditions, such as human amblyopia, in which reorganization of neural circuitries would be beneficial in adult life. These therapeutic approaches bear some similarity to the interventions that have proved successful in promoting recovery from other pathological conditions such as stroke (Maurer & Hensch 2012).…”

Section: Resultsmentioning

confidence: 99%