Subject(s)
Parkinson Disease , Polypharmacy , Death, Sudden , Humans , Parkinson Disease/drug therapy , Risk FactorsABSTRACT
Understanding the mechanisms that influence brain excitability and synchronization provides hope that epileptic seizures can be controlled. In this scenario, non-synaptic mechanisms have a critical role in seizure activity. The contribution of ion transporters to the regulation of seizure-like activity has not been extensively studied. Here, we examined how non-synaptic epileptiform activity (NEA) in the CA1 and dentate gyrus (DG) regions of the hippocampal formation were affected by kainic acid (KA) administration. NEA enhancement in the DG and suppression in area CA1 were associated with increased NKCC1 expression in neurons and severe neuronal loss accompanied by marked glial proliferation, respectively. Twenty-four hours after KA, the DG exhibited intense microglial activation that was associated with reduced cell density in the infra-pyramidal lamina; however, cellular density recovered 7 days after KA. Intense Ki67 immunoreactivity was observed in the subgranular proliferative zone of the DG, which indicates new neuron incorporation into the granule layer. In addition, bumetanide, a selective inhibitor of neuronal Cl(-) uptake mediated by NKCC1, was used to confirm that the NKCC1 increase effectively contributed to NEA changes in the DG. Furthermore, 7 days after KA, prominent NKCC1 staining was identified in the axon initial segments of granule cells, at the exact site where action potentials are preferentially initiated, which endowed these neurons with increased excitability. Taken together, our data suggest a key role of NKCC1 in NEA in the DG.
Subject(s)
Dentate Gyrus/physiopathology , Excitatory Amino Acid Agonists/pharmacology , Kainic Acid/pharmacology , Pyramidal Cells/physiology , Status Epilepticus/physiopathology , Animals , Astrocytes/drug effects , Astrocytes/physiology , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/physiopathology , Cell Count , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Disease Models, Animal , Male , Microglia/drug effects , Microglia/physiology , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Rats, Wistar , Solute Carrier Family 12, Member 2/metabolism , Status Epilepticus/chemically induced , Symporters/metabolism , K Cl- CotransportersABSTRACT
Several lines of evidence point to the modification of firing patterns and of synchronization due to gap junctions (GJs) as having a role in the establishment of epileptiform activity (EA). However, previous studies consider GJs as ohmic resistors, ignoring the effects of intense variations in ionic concentration known to occur during seizures. In addition to GJs, extracellular potassium is regarded as a further important factor involved in seizure initiation and sustainment. To analyze how these two mechanisms act together to shape firing and synchronization, we use a detailed computational model for in vitro high-K(+) and low-Ca(2+) nonsynaptic EA. The model permits us to explore the modulation of electrotonic interactions under ionic concentration changes caused by electrodiffusion in the extracellular space, altered by tortuosity. In addition, we investigate the special case of null GJ current. Increased electrotonic interaction alters bursts and action potential frequencies, favoring synchronization. The particularities of pattern changes depend on the tortuosity and array size. Extracellular potassium accumulation alone modifies firing and synchronization when the GJ coupling is null.
