Synaptic competition in structural plasticity and cognitive function

Connections between neurons can undergo long-lasting changes in synaptic strength correlating with changes in structure. These events require the synthesis of new proteins, the availability of which can lead to cooperative and competitive interactions between synapses for the expression of plasticity. These processes can occur over limited spatial distances and temporal periods, defining dendritic regions over which activity may be integrated and could lead to the physical rewiring of synapses into functional groups. Such clustering of inputs may increase the computational power of neurons by allowing information to be combined in a greater than additive manner. The availability of new proteins may be a key modulatory step towards activity-dependent, long-term growth or elimination of spines necessary for remodelling of connections. Thus, the aberrant growth or shrinkage of dendritic spines could occur if protein levels are misregulated. Indeed, such perturbations can be seen in several mental retardation disorders, wherein either too much or too little protein translation exists, matching an observed increase or decrease in spine density, respectively. Cellular events which alter protein availability could relieve a constraint on synaptic competition and disturb synaptic clustering mechanisms. These changes may be detrimental to modifications in neural circuitry following activity.

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Intracellular calcium stores mediate a synapse-specific form of metaplasticity at hippocampal dendritic spines

10.1101/460568 ◽

2018 ◽

Author(s):

Gaurang Mahajan ◽

Suhita Nadkarni

Keyword(s):

Dendritic Spines ◽

Activity Patterns ◽

Long Term Potentiation ◽

Multiple Time Scales ◽

Calcium Stores ◽

Multiple Time ◽

Additional Layer ◽

Term Potentiation ◽

Activity Dependent

ABSTRACTLong-term plasticity mediated by NMDA receptors supports input-specific, Hebbian forms of learning at excitatory CA3-CA1 connections in the hippocampus. An additional layer of stabilizing mechanisms that act globally as well as locally over multiple time scales may be in place to ensure that plasticity occurs in a constrained manner. Here, we investigate the potential role of calcium (Ca2+) stores associated with the endoplasmic reticulum (ER) in the local regulation of plasticity dynamics at individual CA1 synapses. Our study is spurred by (1) the curious observation that ER is sparsely distributed in dendritic spines, but over-represented in large spines that are likely to have undergone activity-dependent strengthening, and (2) evidence suggesting that ER motility within synapses can be rapid, and accompany activity-regulated spine remodeling. Based on a physiologically realistic computational model for ER-bearing CA1 spines, we characterize the contribution of IP3-sensitive Ca2+ stores to spine Ca2+ dynamics during activity patterns mimicking the induction of long-term potentiation (LTP) and depression (LTD). Our results suggest graded modulation of the NMDA receptor-dependent plasticity profile by ER, which selectively enhances LTD induction. We propose that spine ER can locally tune Ca2+-based plasticity on an as-needed basis, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our model suggests that the presence of ER in the CA1 spine may promote re-use of synapses with saturated strengths.

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Conditions for synaptic specificity during the maintenance phase of synaptic plasticity

10.1101/617928 ◽

2019 ◽

Author(s):

Marco A. Huertas ◽

Todd Charlton Sacktor ◽

Harel Z. Shouval

Keyword(s):

Synaptic Plasticity ◽

Dendritic Spines ◽

Maintenance Phase ◽

Reaction Diffusion ◽

Synaptic Specificity ◽

Degradation Rates ◽

Specific Proteins ◽

Activity Dependent ◽

Term Maintenance

AbstractActivity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse-specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKMζ. However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse-specificity. In this paper we address the issue of synapse-specificity during memory maintenance. Assuming that the long-term maintenance of synaptic plasticity is accomplished by a molecular switch we perform simulations using the reaction-diffusion package in NEURON and analytical calculations to determine the limits of synaptic-specificity during maintenance. Moreover, we explore the effects of the diffusion and degradation rates of proteins and of the geometrical characteristics of dendritic spines on synapse specificty. We conclude that the necessary conditions for synaptic specificity during maintenance require that protein synthesis occurs in dendritic spines and that the activated dendritic spines exhibit small neck diameters.

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MAP2 is differentially phosphorylated in schizophrenia, altering its function

Molecular Psychiatry ◽

10.1038/s41380-021-01034-z ◽

2021 ◽

Author(s):

M. J. Grubisha ◽

X. Sun ◽

M. L. MacDonald ◽

M. Garver ◽

Z. Sun ◽

...

Keyword(s):

Protein Synthesis ◽

Disease Risk ◽

Protein Translation ◽

Synaptic Proteins ◽

Synaptic Protein ◽

Spine Density ◽

Neuronal Structure ◽

Protein Levels ◽

And Function

AbstractSchizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach, we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wild type and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz—that a large proportion of individuals have a “MAP2opathy”—in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

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MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function

10.1101/683912 ◽

2019 ◽

Author(s):

MJ Grubisha ◽

X Sun ◽

ML MacDonald ◽

M Garver ◽

Z Sun ◽

...

Keyword(s):

Protein Synthesis ◽

Disease Risk ◽

Protein Translation ◽

Synaptic Proteins ◽

Synaptic Protein ◽

Spine Density ◽

Neuronal Structure ◽

Protein Levels ◽

And Function

AbstractSchizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into 3 modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz - that a large proportion of individuals have a “MAP2opathy” - in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

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Abl2:cortactin interactions regulate dendritic spine stability via control of a stable filamentous actin pool

10.1101/2020.09.12.294694 ◽

2020 ◽

Author(s):

Juliana E. Shaw ◽

Michaela B. C. Kilander ◽

Yu-Chih Lin ◽

Anthony J. Koleske

Keyword(s):

Dendritic Spines ◽

Dendritic Spine ◽

Actin Filaments ◽

Synaptic Activity ◽

Spine Density ◽

Filamentous Actin ◽

Nonreceptor Tyrosine Kinase ◽

Spine Stability ◽

Small Pool ◽

Activity Dependent

AbstractDendritic spines are enriched with stable and dynamic actin filaments, which determine their structure and shape. Disruption of the Abl2/Arg nonreceptor tyrosine kinase in mice compromises spine stability and size. We provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. Using fluorescence recovery after photobleaching of GFP-actin, we find that disruption of Abl2:cortactin interactions eliminates stable actin filaments in dendritic spines, significantly reducing spine density. A subset of spines remaining after Abl2 depletion retain their stable actin pool and undergo activity-dependent spine enlargement associated with increased cortactin levels. Finally, tonic increases in synaptic activity rescue spine loss upon Abl2 depletion by promoting cortactin enrichment in vulnerable spines. Together, our findings strongly suggest Abl2:cortactin interactions promote spine stability by maintaining pools of stable actin filaments in spines.

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Restoring striatal WAVE-1 improves maze exploration performance of GluN1 knockdown mice

10.1101/341479 ◽

2018 ◽

Author(s):

Yuxiao Chen ◽

Marija Milenkovic ◽

Ali Salahpour ◽

Scott H. Soderling ◽

Amy J. Ramsey

Keyword(s):

Rho Gtpases ◽

Pyramidal Neurons ◽

Medium Spiny Neuron ◽

Long Term Memory ◽

Spine Density ◽

Cognitive Domains ◽

Protein Levels ◽

Y Maze ◽

Hippocampal Ca1

AbstractNMDA receptors are important for cognition and are implicated in neuropsychiatric disorders. GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments. However, how NMDA depletion leads to these effects is unclear. Since Rho GTPases are known to regulate spine density and cognition, we examined the levels of RhoA, Rac1, and Cdc42 signaling proteins. Striatal Rac1-pathway components are reduced in GluN1KD mice, with Rac1 and WAVE-1 deficits at 6 and 12 weeks of age. Concurrently, medium spiny neuron (MSN) spine density deficits are present in mice at these ages. To determine whether WAVE-1 deficits were causal or compensatory in relation to these phenotypes, we intercrossed GluN1KD mice with WAVE-1 overexpressing (WAVE-Tg) mice to restore WAVE-1 levels. GluN1KD-WAVE-Tg hybrids showed rescue of striatal WAVE-1 protein levels and MSN spine density, as well as selective behavioral rescue in the Y-maze and 8-arm radial maze tests. GluN1KD-WAVE-Tg mice expressed normalized WAVE-1 protein levels in the hippocampus, yet spine density of hippocampal CA1 pyramidal neurons was not significantly altered. Our data suggest a nuanced role for WAVE-1 effects on cognition and a delineation of specific cognitive domains served by the striatum. Rescue of striatal WAVE-1 and MSN spine density may be significant for goal-directed exploration and associated long-term memory in mice.

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