<i>Shank3</i>mutations impair electrical synapse scaffolding and transmission in mouse brain

Lautz, Jonathan D.; Zhu, Zhanpeng; He, Speed; Sep, Smith; Jp, Welsh

doi:10.1101/2021.03.25.437056

Cited by 4 publications

(2 citation statements)

References 82 publications

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“…In HC/CTX, these PiSCES did not change with NMDA. The different ratios of Shank isoforms expressed in the three brain structures may partially explain these differences, because Shank3 is highly expressed in the IO ( Lautz et al, 2021 ). Overall, our data demonstrate that proteomic differences at baseline allow glutamate receptors and scaffolds to modify their interactions in response to NMDA stimulation in very different ways, allowing for a diversity of computations across brain regions.…”

Section: Discussionmentioning

confidence: 99%

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states

Lautz¹,

Tsegay²,

Zhu³

et al. 2021

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states

Lautz¹,

Tsegay²,

Zhu³

et al. 2021

Cell Reports

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“…Proteins encoded by genes linked to neurodevelopmental disorders (NDDs) comprise many nodes of the gsPIN [10][11][12] , which leads to the hypothesis that genetic mutations linked to NDDs may subtly alter how the gsPIN processes incoming signals 6,13,14 . Over developmental time, these alterations may lead to synaptic dysfunction, aberrant cellular or connectomic development of the brain, and the social and behavioral abnormalities associated with NDDs 15,16 .…”

Section: Introductionmentioning

confidence: 99%

SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome

Stamenkovic,

Lautz,

Harsh

et al. 2024

Mol Psychiatry

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Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigated how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1 -/y mice, the unstimulated protein interaction networks state resembled that of wildtype littermates stimulated with neurotransmitter agonists, demonstrating resting state pre-activation of signaling networks. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated.We tested whether targeting Fyn in FMR1 -/y mice could modify disease phenotypes, and found that Saracatinib (AZD-0530), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1 -/y mice.However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.

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Synaptic signaling networks encode experience by assuming stimulus-specific and brain-region-specific states

Lautz¹,

Tsegay²,

Zhu³

et al. 2021

Preprint

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A core network of ubiquitously expressed glutamate-synapse-associated proteins mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we sought to classify the diversity of activity-dependent remodeling across brain regions using quantitative protein interaction network (PIN) analysis. We first compared the response of cultured neurons to distinct stimuli, and defined PIN parameters that differentiate input types. We next compared the response of three different brain regions maintained alive in vitro to an identical stimulus, and identified three qualitatively different PIN responses. Finally, we measured the PIN response following associative learning tasks, delay and trace eyeblink conditioning, in three brain regions, and found that the two forms of associative learning are distinguished from each other using brain-region-specific network mechanisms. We conclude that although the PIN of the glutamatergic post-synapse is expressed ubiquitously, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity.

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Shank3mutations impair electrical synapse scaffolding and transmission in mouse brain

Cited by 4 publications

References 82 publications

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states

SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome

Synaptic signaling networks encode experience by assuming stimulus-specific and brain-region-specific states

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