Short-Term Epileptiform Activity Potentiates Excitatory Synapses but Does Not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus In Vitro

Abstract

Even brief epileptic seizures can lead to activity-dependent structural remodeling of neural circuitry. Animal models show that the functional plasticity of synapses and changes in the intrinsic excitability of neurons can be crucial for epileptogenesis. However, the exact mechanisms underlying epileptogenesis remain unclear. We induced epileptiform activity in rat hippocampal slices for 15 min using a 4-aminopyridine (4-AP) in vitro model and observed hippocampal hyperexcitability for at least 1 hour. We tested several possible mechanisms of this hyperexcitability, including changes in intrinsic membrane properties of neurons and presynaptic and postsynaptic alterations. Neither input resistance nor other essential biophysical properties of hippocampal CA1 pyramidal neurons were affected by epileptiform activity. The glutamate release probability also remained unchanged, as the frequency of miniature EPSCs and the paired amplitude ratio of evoked responses did not change after epileptiform activity. However, we found an increase in the AMPA/NMDA ratio, suggesting alterations in the properties of postsynaptic glutamatergic receptors. Thus, the increase in excitability of hippocampal neural networks is realized through postsynaptic mechanisms. In contrast, the intrinsic membrane properties of neurons and the probability of glutamate release from presynaptic terminals are not affected in a 4-AP model.

Maternal Hypoxia Increases the Excitability of Neurons in the Entorhinal Cortex and Dorsal Hippocampus of Rat Offspring

“…Electrophysiological properties of neurons were assessed from the voltage responses to the series of 1500-ms hyperpolarizing and depolarizing current steps with 10–25 pA increments ( Smirnova et al, 2018 ; Postnikova et al, 2019 ; Ergina et al, 2021 ) using custom scripts written in Wolfram Mathematica 12 (Wolfram Research, United States). EC pyramidal neurons were additionally identified by the regular spiking pattern in response to current injection, small afterhyperpolarization, and low steady-state firing frequency (20–40 Hz with 150 pA current injection).…”

The microbiota‐gut‐brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models

“…In particular, exploiting these latter for a deeper understanding of what is observed in vivo. The preparation of brain tissues, in vitro, and their manipulation for multiple biochemical and electrochemical analysis is more accessible to study in detail the neural networks and provide the possibility to perform mechanistic studies on the brain's molecular and cellular mechanisms which is not allowed by classic in vivo models due to their intrinsic complexity 83 . Especially for new antiseizure medications, in vitro models are considered important to link the pharmacokinetics (PK) properties, well predictable using in vivo methods, with the detection of the compounds anticonvulsant properties 84 .…”

“…The preparation of brain tissues, in vitro, and their manipulation for multiple biochemical and electrochemical analysis is more accessible to study in detail the neural networks and provide the possibility to perform mechanistic studies on the brain's molecular and cellular mechanisms which is not allowed by classic in vivo models due to their intrinsic complexity. 83 Especially for new antiseizure medications, in vitro models are considered important to link the pharmacokinetics (PK) properties, well predictable using in vivo methods, with the detection of the compounds anticonvulsant properties. 84 Moreover, to perform neural recordings to get detailed information on brain function and synaptic plasticity, recent in vitro systems offer higher spatial resolution and higher signal-to-noise ratio if compared to in vivo recordings.…”

The Potential Role of Polyamines in Epilepsy and Epilepsy-Related Pathophysiological Changes

“…In the early phases of epileptogenesis, severe pathophysiological alterations appear in the expression of some genes and proteins, GABAergic transmission, the synthesis of neuropeptides, the properties of iGluRs and the availability of some ion channels. Even brief epileptic seizures can generate long-term potentiation (LTP) and increase synaptic efficacy [ 98 , 199 , 200 , 201 , 202 ]. iGluRs are affected by neuronal activity and are involved in regulating synaptic plasticity [ 203 , 204 , 205 , 206 , 207 ].…”