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

Overhoff, Melina; Tellkamp, Frederik; Heß, Simon; Tutas, Janine; Tolve, Marianna; Faerfers, Marcel; Ickert, Lotte; Mohammadi, Milad; Bruyckere, Elodie De; Kallergi, Emmanouela; Vedove, Andrea Dekk; Nikoletopoulou, Vassiliki; Wirth, Brunhilde; Isensee, Jörg; Hucho, Tim; Puchkov, Dmytro; Isbrandt, Dirk; Krueger, Marcus; Kloppenburg, Peter; Kononenko, Natalia L.

doi:10.1101/2022.02.11.480034

Cited by 2 publications

(1 citation statement)

References 98 publications

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“…The enhanced excitation/inhibition ratio onto PC, urged us to further investigate the presence of spontaneous epileptic seizures, as observed in mice with conditional ablation of autophagy in forebrain excitatory neurons (Tang et al, 2014) (Overhoff, 2022) and human patients with mutations in autophagy genes (Fassio et al, 2020). To this end, we performed frontal and parietal electroencephalogram (EEG) recordings in combination with electromyogram (EMG) in three-month-old control (N=8 mice) and PV-atg5KO (N=7 mice) animals for three consecutive light-dark phases.…”

Section: Resultsmentioning

confidence: 99%

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

Chalatsi¹,

Fernandez²,

Scholler

et al. 2022

Preprint

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With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation of atg5 in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission and PV-atg5KO mice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.

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Section: Resultsmentioning

confidence: 99%

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

Chalatsi¹,

Fernandez²,

Scholler

et al. 2022

Preprint

View full text Add to dashboard Cite

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Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis inDrosophilaand Vici Syndrome patients

Deneubourg,

Salimi Dafsari,

Lowe

et al. 2024

Preprint

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Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and ultimately for effective autophagic clearance. VS is characterized by a wide range of neurodevelopmental, neurodegenerative, and neurological features, including epilepsy. Here, we used Drosophila melanogaster to study the importance of epg5 in development, ageing, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression in epg5 Drosophila mutants, in the absence of evident neurodevelopmental abnormalities. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions and propose autophagy stimulating diets as a feasible approach to control EPG5-related pharmacoresistant seizures.

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

Cited by 2 publications

References 98 publications

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis inDrosophilaand Vici Syndrome patients

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