Abstract
Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.
Highlights
Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment
We first tested the hypothesis that severe hypoperfusion/hypoxia in the postictal state suppresses neuronal activity, which is expected to occur under conditions of poor neurovascular coupling[13]
Neuronal activity was measured by 2-photon imaging of somatic calcium activity with GCaMP6f14 simultaneously in hundreds of CA1 pyramidal neurons from awake, head-fixed mice on a treadmill (Fig. 1A)
Summary
Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity. Postictal vasoconstriction-induced hypoperfusion/hypoxia could provide an objective pathophysiological biomarker for defining the postictal p eriod[11] Blocking this long-lasting stroke-like event with pharmacological tools (e.g. L-type calcium channel blockers or cyclooxygenase-2, COX-2, inhibitors) prevents the occurrence of postictal behavioral symptoms following focal s eizures[8]. These results provide insight into how seizures, but more importantly the resulting stroke-like event, lead to long-lasting postictal memory impairments and form the basis for a unique class of epilepsy therapies that target the secondary consequences of seizures when seizure control is not achieved
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