ArticleThe Journal of experimental medicine2020
Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS.
Article in The Journal of experimental medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 79 citations in OpenAlex.
- Cellular and molecular mechanisms of muscle spindle development and function.Physiology (Bethesda, Md.) · 2026Review
- Ia excitatory postsynaptic potentials are potentiated in slow-type motoneurons after a 5-week treadmill endurance training in rats.European journal of applied physiology · 2026Article
- Spinal motoneuron excitability is homeostatically regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.Progress in neurobiology · 2026Article
- Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model.JCI insight · 2026Article
- Disruption of the angiopoietin-like system connects lipid homeostasis and hypothalamic dysfunction in ALS.BMC medicine · 2026Article
- Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.Biology methods & protocols · 2026Article
- Increase in Ia Afferent Synaptic Excitation of SOD1 G93A Mouse Motoneurons by 2-Week Anodal Trans-Spinal Direct Current Stimulation Does Not Ameliorate the Cellular Burden of the Disease.The European journal of neuroscience · 2025Article
- Synaptopathy in the TDP-43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis.The European journal of neuroscience · 2025Article
- Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons.Nature neuroscience · 2025Article
- Synaptic imbalance and increased inhibition impair motor function in SMA.Science advances · 2025Article
- Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration.International journal of molecular sciences · 2025Review
- Sensory Dysfunction in ALS and Other Motor Neuron Diseases: Clinical Relevance, Histopathology, Neurophysiology, and Insights from Neuroimaging.Biomedicines · 2025Review
- Methodological and analytical limitations undermine reported outcomes of spinal DC stimulation in ALS.Frontiers in neurology · 2025Article
- Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.Cell reports · 2024Article
- Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.bioRxiv : the preprint server for biology · 2024Article
- Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.Cell death & disease · 2024Article
- Targeting mitochondrial CaThe Journal of physiology · 2024Review
- Dietary NMN supplementation enhances motor and NMJ function in ALS.Experimental neurology · 2024Article
- Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.PloS one · 2024Article
- Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.Acta neuropathologica · 2023Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
Abstract
Excessive excitation is hypothesized to cause motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS), but actual proof of hyperexcitation in vivo is missing, and trials based on this concept have failed. We demonstrate, by in vivo single-MN electrophysiology, that, contrary to expectations, excitatory responses evoked by sensory and brainstem inputs are reduced in MNs of presymptomatic mutSOD1 mice. This impairment correlates with disrupted postsynaptic clustering of Homer1b, Shank, and AMPAR subunits. Synaptic restoration can be achieved by activation of the cAMP/PKA pathway, by either intracellular injection of cAMP or DREADD-Gs stimulation. Furthermore, we reveal, through independent control of signaling and excitability allowed by multiplexed DREADD/PSAM chemogenetics, that PKA-induced restoration of synapses triggers an excitation-dependent decrease in misfolded SOD1 burden and autophagy overload. In turn, increased MN excitability contributes to restoring synaptic structures. Thus, the decrease of excitation to MN is an early but reversible event in ALS. Failure of the postsynaptic site, rather than hyperexcitation, drives disease pathobiochemistry.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.