Neuronal activity recruits the CRTC1/CREB axis to drive transcription-dependent autophagy for maintaining late-phase LTD

Pan, Yue; He, Xingzhi; Li, Cuicui; Li, Yanjun; Li, Wenwen; Zhang, Hanbin; Wang, Yan; Zhou, Guozhong; Yang, Jing; Li, Jiarui; Qu, Jing; Wang, Hao; Gao, Zhihua; Shen, Ying; Li, Tao; Hu, Hailan; Ma, Hongxia

doi:10.1016/j.celrep.2021.109398

Cited by 32 publications

(17 citation statements)

References 72 publications

(130 reference statements)

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“…Additionally, Compans et al found that autophagy is required for the degradation of T19-phosphorylated form of PSD95 in NMDAR-LTD induction, which triggers a depletion of PSD95 from synapses and eventually increases short-term plasticity to improve neuronal responsiveness of depressed synapses [ 84 ]. A most recent study has shown that constitutive induction of mTOR-dependent autophagy rescues the prevention of NMDAR-LTD induced by disrupting synergistic action of CREB and CRTC1, two essential transcriptional factors for late-phase long-term synaptic potentiation [ 85 ]. These findings reveal the previously unrecognized functions of autophagy in the regulation of synaptic plasticity and memory (Fig.…”

Section: Autophagy Regulates Presynaptic and Postsynaptic Development And Synaptic Activitymentioning

confidence: 99%

Autophagy deficiency in neurodevelopmental disorders

Deng

Zhou

et al. 2021

Cell Biosci

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Autophagy is a cell self-digestion pathway through lysosome and plays a critical role in maintaining cellular homeostasis and cytoprotection. Characterization of autophagy related genes in cell and animal models reveals diverse physiological functions of autophagy in various cell types and tissues. In central nervous system, by recycling injured organelles and misfolded protein complexes or aggregates, autophagy is integrated into synaptic functions of neurons and subjected to distinct regulation in presynaptic and postsynaptic neuronal compartments. A plethora of studies have shown the neuroprotective function of autophagy in major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Recent human genetic and genomic evidence has demonstrated an emerging, significant role of autophagy in human brain development and prevention of spectrum of neurodevelopmental disorders. Here we will review the evidence demonstrating the causal link of autophagy deficiency to congenital brain diseases, the mechanism whereby autophagy functions in neurodevelopment, and therapeutic potential of autophagy.

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Section: Autophagy Regulates Presynaptic and Postsynaptic Development And Synaptic Activitymentioning

confidence: 99%

Autophagy deficiency in neurodevelopmental disorders

Deng

Zhou

et al. 2021

Cell Biosci

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“…This role of autophagy in neuronal homeostasis is especially crucial at synapses, which possess high metabolic demands and are vulnerable to accumulated damage and stress (reviewed in ( 15 )). Autophagy has been described to regulate the degradation of several pre- and postsynaptic proteins ( 12 , 54 – 56 ), axonal ER ( 13 ), and synaptic mitochondria ( 14 , 57 ) and, is, thereby, crucial for the regulation of synaptic plasticity, including long-term depression (LTD) ( 11 , 25 , 58 , 59 ). Intriguingly, here we find that ATG5-mediated autophagy does not primarily contribute to the regulation of bulk levels of SV and/or mitochondrial proteins in excitatory or inhibitory neurons i n-vivo .…”

Section: Discussionmentioning

confidence: 99%

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Overhoff

Tellkamp

Heß

et al. 2022

Preprint

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Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

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“…TORC also acts at least in part by assisting in the recruitment of CBP to CREB. Meanwhile, CREB-regulated transcription coactivator 1(CRTC1) can also dephosphorylate at Ser-151 and is recruited from cytoplasm to the nucleus, where it competes with FXR (fed-state sensing nuclear receptor) for binding to CREB and drives autophagy gene expression (Pan et al, 2021). Some studies have shown that Ca 2+ influx activates CREB through TRPC6, which is an important transcription factor linked to neuronal survival.…”

Section: Nmdar-dependent Neuroprotection In Epilepsymentioning

confidence: 99%

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Chen

Liu

et al. 2022

Front. Mol. Neurosci.

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Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

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Neuronal activity recruits the CRTC1/CREB axis to drive transcription-dependent autophagy for maintaining late-phase LTD

Cited by 32 publications

References 72 publications

Autophagy deficiency in neurodevelopmental disorders

Autophagy deficiency in neurodevelopmental disorders

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

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