Mechanisms that communicate features of neuronal activity to the genome

Heinz, Daniel A; Bloodgood, Brenda L.

doi:10.1016/j.conb.2020.03.002

Cited by 12 publications

(8 citation statements)

References 53 publications

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“…Nevertheless, many mechanisms mediating responses to elevated extracellular KCl also prove necessary for similar in vivo functions. Seizures, sensory stimuli, and learning events induce IEGs likewise induced by extracellular KCl ( Morgan et al., 1987 ; Hunt et al., 1988 ; Guzowski et al., 2001 ; Lyons and West, 2011 ; West and Greenberg, 2011 ; Mukherjee et al., 2018 ; Heinz and Bloodgood, 2020 ). Furthermore, while sustained global depolarization by elevated KCl is not a feature of healthy neuronal signaling, it is a proposed mechanism of Leão’s spreading depression of neuronal activity ( Leao, 1944 ; Grafstein, 1956 ; Somjen, 2001 ; de Curtis et al., 2018 ).…”

Section: Strengths and Limitations Of Extracellular Kcl Treatmentmentioning

confidence: 99%

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium

2020

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Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments in vitro are criticized for being poor representatives of in vivo phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment in vitro, the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.

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Section: Strengths and Limitations Of Extracellular Kcl Treatmentmentioning

confidence: 99%

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium

2020

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“…Diverse signal transduction and molecular pathways are responsible for translating changes in neuronal activity to cellular modifications in neurons, including altered neurite volume, synapse number, and gene expression (Chiang et al, 2009; Faust et al, 2021; Heinz and Bloodgood, 2020; Lee and Fields, 2021). Our data suggested that perturbing electrical activity had both shared and differential effects on synapse formation across distinct neuronal class (ORN vs. PN vs. LN): reduced electrical activity reduced synapse number in all classes, but increased electrical activity affected synapse number in some (ORN) but not all (PN and LN) neuronal classes.…”

Section: Resultsmentioning

confidence: 99%

Different olfactory neuron classes use distinct temporal and molecular programs to complete synaptic development

Aimino

DePew

Restrepo

et al. 2022

Preprint

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Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphological maturation. Moreover, it remains unknown if neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and using identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage of the Drosophila antennal lobe, a model olfactory circuit with remarkable genetic access and synapse-level resolution. Using tissue-specific genetic labeling of active zones, we performed a quantitative analysis of synapse formation in multiple classes of neurons throughout development and adulthood. We found that olfactory receptor neurons (ORNs), projection neurons (PNs), and local interneurons (LNs) each have unique time-courses of synaptic development, addition, and refinement, demonstrating that each class follows a distinct developmental program. This raised the possibility that these classes may also have distinct molecular requirements for synapse formation. We genetically altered neuronal activity in each neuronal subtype and observed differing effects on synapse number based on the neuronal class examined. Silencing neuronal activity in ORNs, PNs, and LNs impaired synaptic development but only in ORNs did enhancing neuronal activity influence synapse formation. ORNs and LNs demonstrated similar impairment of synaptic development with enhanced activity of a master kinase, GSK-3β, suggesting that neuronal activity and GSK-3β kinase activity function in a common pathway. ORNs also, however, demonstrated impaired synaptic development with GSK-3β loss-of-function, suggesting additional activity-independent roles in development. Ultimately, our results suggest that the requirements for synaptic development are not uniform across all neuronal classes with considerable diversity existing in both their developmental timeframes and molecular requirements. These findings provide novel insights into the mechanisms of synaptic development and lay the foundation for future work determining their underlying etiologies.

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“…To identify proteins that undergo activity-dependent changes in nuclear abundance, we silenced neurons for 1 h with the voltage-gated sodium channel antagonist tetrodotoxin (TTX) or stimulated neurons for 1 h with bicuculline (Bic), which inhibits GABA A receptors and drives glutamatergic transmission. We also inhibited protein synthesis using cycloheximide (CHX) in these experiments because many of the genes that are rapidly transcribed and translated in response to activity encode nuclear proteins ( Yap and Greenberg, 2018 ; Heinz and Bloodgood, 2020 ; Alberini, 2009 ). We were concerned that the translation of activity-dependent genes would overshadow, and thereby hinder the detection of, the upstream changes that occur in the nuclear proteome resulting from alterations in nuclear protein localization or stability.…”

Section: Resultsmentioning

confidence: 99%

Neuronal activity regulates the nuclear proteome to promote activity-dependent transcription

Herbst

Deng

Wohlschlegel

et al. 2021

Journal of Cell Biology

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The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. Although recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons.

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Mechanisms that communicate features of neuronal activity to the genome

Cited by 12 publications

References 53 publications

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium

Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium

Different olfactory neuron classes use distinct temporal and molecular programs to complete synaptic development

Neuronal activity regulates the nuclear proteome to promote activity-dependent transcription

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