Abstract
Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, we found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Action Potentials / drug effects
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Action Potentials / physiology
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Age Factors
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Animals
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Animals, Newborn
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Biophysical Phenomena / physiology
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Biophysics
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Brain Injuries / complications*
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Brain Injuries / pathology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Cerebral Cortex / physiopathology*
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Cyclic Nucleotide-Gated Cation Channels / genetics
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Cyclic Nucleotide-Gated Cation Channels / metabolism
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Disease Models, Animal
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Electric Capacitance
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Electric Stimulation
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Electroencephalography
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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In Vitro Techniques
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Ion Channels / genetics
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Ion Channels / metabolism
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Light
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Lysine / analogs & derivatives
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Lysine / metabolism
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Membrane Potentials / genetics
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Microscopy, Confocal
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Models, Neurological
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Neural Inhibition / genetics
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Neural Pathways / physiology*
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Neurons / drug effects
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Neurons / physiology
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Optogenetics*
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Patch-Clamp Techniques
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Rats
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Rats, Sprague-Dawley
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Seizures / etiology*
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Spectrum Analysis
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Thalamus / physiology*
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Wakefulness / genetics
Substances
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Cyclic Nucleotide-Gated Cation Channels
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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Ion Channels
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Luminescent Proteins
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Camk2a protein, rat
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biocytin
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Lysine