Paradoxical Enhancement of Fear Extinction Memory and Synaptic Plasticity by Inhibition of the Histone Acetyltransferase p300

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, synaptic plasticity, and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1 mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory.

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IGF-1 facilitates extinction of conditioned fear

10.1101/2020.04.15.042788 ◽

2020 ◽

Author(s):

José A. Noriega-Prieto ◽

Laura E. Maglio ◽

Irene B. Maroto ◽

Jesús Martin-Cortecero ◽

Antonio Muñoz-Callejas ◽

...

Keyword(s):

Prefrontal Cortex ◽

Synaptic Plasticity ◽

Animal Behavior ◽

Pyramidal Neurons ◽

Conditioned Fear ◽

Fear Extinction ◽

Neuronal Firing ◽

Infralimbic Cortex ◽

Regulatory Processes ◽

Extinction Memory

SUMMARYInsulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, degenerative diseases, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal activity in many areas of the brain, its effect on synaptic plasticity and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the infralimbic cortex. Besides, IGF-1 mediates a long-term depression of both inhibitory and excitatory synaptic transmission that results in a longterm potentiation of the postsynaptic potentials. We demonstrate that these synaptic and intrinsic regulatory processes mediated by IGF-1 favor the fear extinction memory. These results show novel functional consequences of IGF-1 signaling on animal behavior tasks dependent on the prefrontal cortex, revealing IGF-1 as a key element in the control of the fear extinction memory.Impact StatementIGF-1 modulates the neuronal firing and synaptic plasticity in infralimbic cortex, favoring the extinction memory

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Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

10.26226/morressier.5ebd45acffea6f735881ae71 ◽

2020 ◽

Author(s):

Paul Robert Marshall

Keyword(s):

Rna Editing ◽

Dna Structure ◽

Fear Extinction ◽

Extinction Memory ◽

Editing Enzyme

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Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity

Nature Communications ◽

10.1038/s41467-021-24950-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yi Zhang ◽

Kyle Brown ◽

Yucong Yu ◽

Ziad Ibrahim ◽

Mohamad Zandian ◽

...

Keyword(s):

Phase Separation ◽

Cell Nucleus ◽

Active Site ◽

Histone Acetyltransferase ◽

Histone H3 ◽

Catalytic Core ◽

Cellular Processes ◽

Storage Pool ◽

Core Components ◽

Acetyltransferase P300

AbstractThe transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the histone acetyltransferase (HAT) domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.

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