AMPA/kainate receptor-mediated downregulation of GABAergic synaptic transmission by calcineurin after seizures in the developing rat brain
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Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
Published on: August 15, 2017
Russell M Sanchez1, Weimin Dai, Rachel E Levada
1Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Insights
Hypoxia causes seizures in newborns, often resistant to drugs. This study identifies calcineurin (CaN) as a key factor in this process, offering potential new treatments for pediatric epilepsy.
Area of Science:
- Neuroscience
- Epileptology
- Developmental Neuroscience
Background:
- Hypoxia is a primary cause of perinatal seizures, frequently unresponsive to standard anticonvulsants.
- This suggests unique age-specific mechanisms driving epileptogenesis in immature brains.
Purpose of the Study:
- To investigate the role of calcineurin (CaN) in hypoxia-induced seizures in immature rats.
- To identify molecular pathways involved in seizure development and potential therapeutic targets.
Main Methods:
- Utilized a rat model of hypoxia-induced seizures.
- Measured calcineurin (CaN) activation, GABA(A) receptor (GABA(A)R) inhibition, and AMPA receptor (AMPAR) activity.
- Administered CaN inhibitors (FK-506) and AMPAR antagonists (NBQX, GYKI 52466) in vivo and in vitro.
Main Results:
- Hypoxic seizures activated CaN in the hippocampus (area CA1), leading to reduced GABA(A)R inhibition.
- CaN activation was dependent on Ca2+-permeable AMPARs.
- CaN inhibition with FK-506 suppressed seizures and blocked CaN expression.
- Dephosphorylation of GABA(A)R beta2/3 subunits was observed post-seizure.
Conclusions:
- Ca2+-permeable AMPARs and CaN form a novel plasticity pathway regulating inhibitory transmission.
- This pathway is implicated in epileptogenesis in the immature brain.
- Targeting CaN may offer a therapeutic strategy for hypoxia-induced seizures in neonates.
Abstract:
Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABA(A) receptor (GABA(A)R)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable AMPA receptors (AMPARs), because the upregulation of CaN activation and GABA(A)R inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABA(A)R beta2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.
