Multiomics of early epileptogenesis in mice reveals phosphorylation and dephosphorylation-directed growth and
Mariella Hurtado Silva1, Ashley J van Waardenberg2, Aya Mostafa3
1Synapse Proteomics, Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia.
Abstract:
To investigate the phosphorylation-based signaling and protein changes occurring early in epileptogenesis, the hippocampi of mice treated with pilocarpine were examined by quantitative mass spectrometry at 4 and 24 h post-status epilepticus at vast depth. Hundreds of posttranscriptional regulatory proteins were the major early targets of increased phosphorylation. At 24 h, many protein level changes were detected and the phosphoproteome continued to be perturbed. The major targets of decreased phosphorylation at 4 and 24 h were a subset of postsynaptic density scaffold proteins, ion channels, and neurotransmitter receptors. Many proteins targeted by dephosphorylation at 4 h also had decreased protein abundance at 24 h, indicating a phosphatase-mediated weakening of synapses. Increased translation was indicated by protein changes at 24 h. These observations, and many additional indicators within this multiomic resource, suggest that early epileptogenesis is characterized by signaling that stimulates both growth and a homeostatic response that weakens excitability.
Insights
Early epilepsy development involves significant protein changes and altered phosphorylation in the hippocampus. These molecular shifts suggest a complex interplay of growth stimulation and excitability reduction.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Epileptogenesis involves complex molecular alterations.
- Understanding early signaling pathways is crucial for therapeutic development.
Purpose of the Study:
- To investigate early phosphorylation-based signaling and protein changes during epileptogenesis.
- To identify molecular targets affected in the initial stages of seizure development.
Main Methods:
- Quantitative mass spectrometry was employed on mouse hippocampi.
- Analysis was performed at 4 and 24 hours post-pilocarpine-induced status epilepticus.
Main Results:
- Hundreds of posttranscriptional regulatory proteins showed increased phosphorylation early on.
- Dephosphorylation of synaptic proteins, ion channels, and receptors was observed, correlating with decreased protein abundance.
- Increased protein translation and perturbed phosphoproteome were evident at 24 hours.
Conclusions:
- Early epileptogenesis involves dynamic phosphorylation signaling affecting synaptic components.
- A phosphatase-mediated weakening of synapses occurs, alongside increased translation.
- These early changes suggest a dual response promoting growth and reducing excitability.
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