Intrinsic and synaptic properties of hippocampal CA1 pyramidal neurons of the Wistar Audiogenic Rat (WAR) strain, a genetic model of epilepsy

Alexandra Olimpio Siqueira Cunha,Cesar Celis Ceballos,Rodrigo Felipe De Oliveira Pena,Antonio Carlos Roque,Norberto Garcia-Cairasco,Ricardo Maurício Leão,José Antonio Cortes De Oliveira,Júnia Lara De Deus

doi:10.1038/s41598-018-28725-y

Alexandra Olimpio Siqueira Cunha, Cesar Celis Ceballos + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-28725-y

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Abstract

Despite the many studies focusing on epilepsy, a lot of the basic mechanisms underlying seizure susceptibility are mainly unclear. Here, we studied cellular electrical excitability, as well as excitatory and inhibitory synaptic neurotransmission of CA1 pyramidal neurons from the dorsal hippocampus of a genetic model of epilepsy, the Wistar Audiogenic Rat (WARs) in which limbic seizures appear after repeated audiogenic stimulation. We examined intrinsic properties of neurons, as well as EPSCs evoked by Schaffer-collateral stimulation in slices from WARs and Wistar parental strain. We also analyzed spontaneous IPSCs and quantal miniature inhibitory events. Our data show that even in the absence of previous seizures, GABAergic neurotransmission is reduced in the dorsal hippocampus of WARs. We observed a decrease in the frequency of IPSCs and mIPSCs. Moreover, mIPSCs of WARs had faster rise times, indicating that they probably arise from more proximal synapses. Finally, intrinsic membrane properties, firing and excitatory neurotransmission mediated by both NMDA and non-NMDA receptors are similar to the parental strain. Since GABAergic inhibition towards CA1 pyramidal neurons is reduced in WARs, the inhibitory network could be ineffective to prevent the seizure-dependent spread of hyperexcitation. These functional changes could make these animals more susceptible to the limbic seizures observed during the audiogenic kindling.

Highlights

Epilepsy is a set of neurological disorders that has as a common symptom the appearance of sudden events of hypersynchronization and hyperactivity of neurons[1]
Upon repetition of the sound, the animals start to exhibit behavioral patterns typical of limbic seizures, with epileptiform discharges spreading through amygdala, hippocampus and auditory cortex, a phenomenon known as limbic recruitment[5,6,7,8]
CA1 pyramidal neurons from Wistar Audiogenic Rats (WARs) (n = 17) and Wistar rats (n = 14) had similar firing patterns (Fig. 1A) typical to what has been previously reported for CA1 pyramidal neurons (Wheeler et al, 2015)

Summary

Introduction

Epilepsy is a set of neurological disorders that has as a common symptom the appearance of sudden events of hypersynchronization and hyperactivity of neurons[1]. Acute audiogenic seizures are generalized reflex tonic-clonic seizures induced by a high intensity sound (e.g. 120 dB), regardless of its frequency. They are rare in humans, audiogenic seizures are very well characterized in several strains of rodents, with stereotyped behaviors and epileptiform electroencephalographic activity initially restricted to the auditory brainstem[3,4,5]. Upon repetition of the sound, the animals start to exhibit behavioral patterns typical of limbic seizures, with epileptiform discharges spreading through amygdala, hippocampus and auditory cortex, a phenomenon known as limbic recruitment[5,6,7,8]. Restin g m em b ran e p o te n tia l (m V ) # APs # APs

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