Synapse development organized by neuronal activity-regulated immediate-early genes

Kim, Seungjoon; Kim, Hyeonho; Um, Ji Won

doi:10.1038/s12276-018-0025-1

Cited by 59 publications

(49 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After activation, SRF propagates in neurons an immediate early gene (IEG) response resulting in rapid (within minutes) but transient upregulation of target genes including cFos, Egr1, Egr2, Egr3, and, for example, Arc . Since many SRF effector genes encode TFs, this results in a second gene expression wave involved in modulation of learning and memory, synaptic plasticity as well as neuro‐behavioral changes such as hyperactivity and modulated anxiety . So far, selected IEGs such as cFos, cJun, and Egr1 were found upregulated by TBI in humans and in rodent TBI models .…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Since many SRF effector genes encode TFs, this results in a second gene expression wave involved in modulation of learning and memory, synaptic plasticity as well as neuro-behavioral changes such as hyperactivity and modulated anxiety. [23][24][25] So far, selected IEGs such as cFos, cJun, and Egr1 were found upregulated by TBI in humans 26,27 and in rodent TBI models. [28][29][30][31][32] However, a functional role of SRF or one of these IEGs in TBI has not been described.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

Förstner

Knöll

2020

FASEB j.

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is one of the most frequent causes of brain injury and mortality in young adults with detrimental sequelae such as cognitive impairments, epilepsy, and attention‐deficit hyperactivity disorder. TBI modulates the neuronal excitability resulting in propagation of a neuronal activity‐driven gene expression program. However, the impact of such neuronal activity mediated gene expression in TBI has been poorly studied. In this study we analyzed mouse mutants of the prototypical neuronal activity‐dependent transcription factor SRF (serum response factor) in a weight‐drop TBI model. Neuron‐restricted SRF deletion elevated TBI inflicted mortality suggesting a neuroprotective SRF function during TBI. Behavioral inspection uncovered elevated locomotor activity in Srf mutant mice after TBI in contrast to hypoactivity observed in wild‐type littermates. This indicates an SRF role in modulation of TBI‐associated alterations in locomotor activity. Finally, induction of a neuronal activity induced gene expression program composed of immediate early genes (IEGs) such as Egr1, Egr2, Egr3, Npas4, Atf3, Arc, Ptgs2, and neuronal pentraxins (Nptx2) was compromised upon SRF depletion. Overall, our data show a role of neuronal activity‐mediated gene transcription during TBI and suggest a molecular link between TBI and such post‐TBI neurological comorbidities involving hyperactivity phenotypes.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

Förstner

Knöll

2020

FASEB j.

View full text Add to dashboard Cite

show abstract

“…Thus, spontaneous network activity and molecular/synaptic modifications are reciprocally connected (Bains et al 1999). Importantly, IEG expression is rapidly and selectively upregulated by behavioral experience and neuronal activity in subsets of neurons in specific brain regions which are associated with learning and memory (Kubik et al 2007;Kim et al 2018;Minatohara et al 2016). It is particularly interesting that spontaneous activity in neuronal networks can induce reorganization of synaptic connections, thereby continuously updating the network status (Tsukamoto-Yasui et al 2007), as it virtually happens in the CA1 circuitry of VH slices, where the increase in amplitude of SPWs is associated with specific molecular and synaptic reorganization.…”

Section: Implications Of Iegs Expression For Spws Functionmentioning

confidence: 99%

Increased molecular plasticity along the septotemporal axis of the hippocampus is associated with network functioning

Sotiriou

Angelatou

Papatheodoropoulos

2019

Preprint

View full text Add to dashboard Cite

Molecular plasticity crucially supports adaptive cellular and network functioning in the brain. Variations in molecular plasticity may yield important differences in neuronal network dynamics between discrete brain subregions. In the present study we show that the gradual development of sharp waves (SPWs), a spontaneous network activity that is organized under normal in vitro conditions in the CA1 field of ventral but not dorsal hippocampal slices, is associated with region selective molecular reorganization. In particular, increased levels of mRNAs for specific GABA A receptor subunits (α1, β2, γ2) occurred in ventral hippocampal CA1 field during the development of SPWs. These mRNA changes were followed by a clear increase in GABA A receptor number in ventral hippocampus, as shown by [ 3 H]muscimol binding. An increase in mRNAs was also observed in dorsal slices for α2 and α5 subunits, not followed by quantitative GABA A receptor changes. Furthermore, full development of SPWs in the CA1 field (at 3 hours of slice maintenance in vitro) was followed by increased expression of immediate early genes c-fos and zif-268 in ventral hippocampal slices (measured at 5 hours in vitro). No change in c-fos and zif-268 levels is observed in the CA1 field of dorsal slices, which do not develop spontaneous activity. These results suggest that generation of SPWs could trigger specific molecular reorganization in the VH that may be related to the functional roles of SPWs. Correspondingly, the revealed increased potentiality of the ventral hippocampus for molecular reorganization may provide a clue to mechanisms that underlie the regulated emergence of SPWs along the longitudinal axis of the hippocampus. Furthermore, the present evidence suggests that dynamic tuning between spontaneous neuronal activity and molecular organization may importantly contribute to the functional segregation/heterogeneity seen along the hippocampus.

show abstract

“…These connections facilitate neuroplastic events that underlie learning and memory, critical aspects of cognitive function often perturbed in neuropsychiatric illnesses [2,3]. Neuronal signaling is mediated by fast and slow transmission events, encompassing receptors, ligands, ions, enzymes, and other substrates [1,[4][5][6][7]. These elements are spatially arranged in subcellular microdomains, facilitating juxtaposition of proteins that coordinate various biological processes.…”

Section: Introductionmentioning

confidence: 99%

“…These elements are spatially arranged in subcellular microdomains, facilitating juxtaposition of proteins that coordinate various biological processes. For example, synaptic transmission is modulated via release of neurotransmitter into the synaptic cleft, where receptors are activated and the postsynaptic cell modulated via electrical and chemical signals [1,[4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Funk

Labilloy

Reigle

et al. 2020

Preprint

View full text Add to dashboard Cite

Running title -PSD-95 protein-protein interactions in human brainThe overarching goal of this exploratory study is to link subcellular microdomain specific protein-protein interactomes with big data analytics. We isolated postsynaptic density-95 (PSD-95) complexes from four human brain regions and compared their protein interactomes using multiple bioinformatics techniques. We demonstrate that human brain regions have unique postsynaptic protein signatures that may be used to interrogate perturbagen databases. Assessment of our hippocampal signature using the iLINCS database yielded several compounds with recently characterized "off target" effects on protein-protein interactions in the posynaptic density compartment. Acknowledgments:We would like to thank all those that have supported this research: the L.I.F.E. Foundation, UCNI pilot award, Lindsay Brinkmeyer Schizophrenia Research Fund, Center for Clinical and Translational Science Training (CCTST), and NIH grant MH107916. The MS data was acquired in the University of Cincinnati Proteomics Laboratory on a mass spectrometer funded in part through the NIH S10 shared instrumentation grant RR027015.Altering the expression of PSD-95 protein significantly changes synaptic structure and function, including molecular correlates of learning and memory, long-term potentiation (LTP) and long-term depression (LTD). For example, PSD-95 overexpression increases the amplitude of excitatory postsynaptic currents (EPSCs), to the extent that additional stimulus is unable to further strengthen LTP [13][14][15][16][17]. In contrast, PSD-95 knockdown disrupts postsynaptic density structure and suppresses EPSCs, consistent with a role for PSD-95 in synaptic fidelity [18][19][20]. Further highlighting the importance of PSD-95 in the synapse, knockout of PSD-95 in mice and genomic variants within postsynaptic density hub proteins are particularly implicated in neuropsychiatric disorders such as schizophrenia and autism [21,22].To investigate excitatory postsynaptic protein hubs, we targeted PSD-95 due to its high level of localization to the postsynaptic density (~95%), its well-characterized role as a hub protein, and the large number of constituents in its protein interactome (~1000) [23][24][25]. We designed a series of experiments to examine brain region-specific excitatory postsynaptic proteomes to answer the following questions. 1) Do postsynaptic protein-protein interactions differ by brain region? 2) Can we accurately detect and separate samples based on these differences? and 3) Can region-specific protein interactomes inform functional differences? For these experiments we used four human brain regions (anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus (HPC), and superior temporal gyrus (STG)) from 3 well-matched control male subjects from the Alabama Brain Collection. A total of 289 proteins were identified as part of a PSD-95 protein interactome that were present across all four brain regions.We hypothesize that there is region-specific ...

show abstract

Synapse development organized by neuronal activity-regulated immediate-early genes

Cited by 59 publications

References 93 publications

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

Increased molecular plasticity along the septotemporal axis of the hippocampus is associated with network functioning

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Contact Info

Product

Resources

About