Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam.

Yuan-Hao Chen,Jonathan P Miller,Yung-Hsiao Chiang,Hsin-I Ma,Tung-Tai Kuo,Eagle Yi-Kung Huang,Yu-Ching Chou,Barry J Hoffer

doi:10.18632/oncotarget.23923

Abstract

AimTo determine the precise effects of post-traumatic seizure activity on hippocampal processes, we induced seizures at various intervals after traumatic brain injury (TBI) and analyzed plasticity at CA1 Schaffer collateral synapses.Material and MethodsRats were initially separated into two groups; one exposed solely to fluid percussion injury (FPI) at 2 Psi and the other only receiving kainic acid (KA)-induced seizures without FPI. Electrophysiological (ePhys) studies including paired-pulse stimulation for short-term presynaptic plasticity and long-term potentiation (LTP) of CA1 Schaffer collateral synapses of the hippocampus for post-synaptic function survey were followed at post-event 1 hour, 3 and 7 days respectively. Additional rats were exposed to three seizures at weekly intervals starting 1 week or 2 weeks after TBI and compared with seizures without TBI, TBI without seizures, and uninjured animals. An additional group placed under the same control variables were treated with levetiracetam prior to seizure induction. The ePhys studies related to post-TBI induced seizures were also followed in these additional groups.ResultsSeizures affected the short- and long-term synaptic plasticity of the hippocampal CA3-CA1 pathway. FPI itself suppressed LTP and field excitatory post synaptic potentials (fEPSP) in the CA1 Schaffer collateral synapses; KA-induced seizures that followed FPI further suppressed synaptic plasticity. The impairments in both short-term presynaptic and long-term plasticity were worse in the rats in which early post-TBI seizures were induced than those in which later post-TBI seizures were induced. Finally, prophylactic infusion of levetiracetam for one week after FPI reduced the synaptic plasticity deficits in early post-TBI seizure animals.ConclusionOur data indicates that synaptic plasticity (i.e., both presynaptic and postsynaptic) suppression occurs in TBI followed by a seizure and that the interval between the TBI and seizure is an important factor in the severity of the resulting deficits. Furthermore, the infusion of prophylactic levetiracetam could partially reverse the suppression of synaptic plasticity.

Highlights

Traumatic brain injury (TBI) frequently leads to severe and persistent neurological deficits that can result in considerable morbidity
Electrophysiological studies including paired-pulse stimulation for short-term presynaptic plasticity and long-term potentiation (LTP) of cornu ammonis 1 (CA1) Schaffer collateral synapses of the hippocampus for postsynaptic function survey were followed at post-event 1 hour, 3 and 7 days respectively
Short-term plasticity of hippocampal CA1CA3 Schaffer collateral synapses is affected by kainic acid (KA)-induced seizures and by fluid percussion in injury (Figure 1)

Summary

Introduction

Traumatic brain injury (TBI) frequently leads to severe and persistent neurological deficits that can result in considerable morbidity. There is evidence that the interval between a TBI and a post-TBI seizure may impact both the severity of TBI comorbidities and epileptogenesis [12, 13], and early seizures (defined as occurring within one week after injury) [14] may be associated with worse memory outcome than seizures that occur remotely. If this is the case, aggressive seizure prophylaxis may be important for improved outcome

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