Pattern and Pharmacology of Propagating Epileptiform Activity in Mouse Cerebral Cortex

The majority of patients showing neuronal migration disorders in cortical structures suffer from pharmaco-resistant epilepsy. In order to study the molecular and cellular mechanisms underlying this pronounced hyperexcitability, we used an animal model of focal cortical dysplasia demonstrating structural malformations which resemble the human pathology of microgyria. Neocortical slices prepared from adult rats, which at the day of birth received a cortical freeze lesion, were analysed in vitro with an array of eight extracellular recording electrodes to investigate the pattern and pharmacology of propagating epileptiform activity in microgyric cortex. In cortical slices exhibiting neuronal migration disorders, orthodromic synaptic stimulation elicited late recurrent activity and early epileptiform responses that spread with 0.06 m/s over > or = 3.5 mm across the cortex. Application of a N-methyl-D-aspartate (NMDA) antagonist blocked the late recurrent activity, but not the propagation of the early epileptiform responses. The latter were blocked by an (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, indicating that the spread of this activity was predominantly mediated by activation of AMPA receptors. A very similar response pattern could be observed in neocortical slices obtained from untreated age-matched control rats, when the slice was partially disinhibited by bath-application of 5 microM bicuculline methiodide. Stimulus-evoked epileptiform signals recorded in disinhibited slices propagated with 0.08 m/s across the cortex and showed the same sensitivity to ionotropic glutamate antagonists as in dysplastic cortex. Our results indicate that widespread structural and/or functional modifications of the AMPA receptor and possibly also of the gamma-amino-butyric acid type A receptor contribute to the pronounced hyperexcitability in dysplastic cortex.

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Section: Discussionsupporting

confidence: 88%

Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings

Luhmann

Raabe

Qü³

et al. 1998

Eur J of Neuroscience

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“…Application of a GABA A antagonist through a microdialysis probe induced paroxysmal field potentials that were blocked by an AMPA antagonist, but not by APV, indicating that under these conditions the spread of pathophysiological activity is predominantly mediated by non-NMDA receptors (Castro-Alamancos & Borrell, 1995). This report and our own observations in disinhibited neocortical slices (see also Alefeld et al, 1998) suggest that a GABA A receptor dysfunction may also contribute to the pronounced hyperexcitability in cortex with NMDs. This hypothesis is supported by our intracellular recordings in rat dysplastic cortex, which demonstrated only weak polysynaptic inhibitory postsynaptic potentials (IPSPs) with smaller peak conductances when compared to IPSPs recorded in sham-operated cortex .…”

Section: Discussionsupporting

confidence: 59%

Characterization of Neuronal Migration Disorders in Neocortical Structures. II. Intracellular In Vitro Recordings

Luhmann

Karpuk

Qü

et al. 1998

Journal of Neurophysiology

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Neuronal migration disorders (NMD) are involved in a variety of different developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dysplastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebral cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in cortical slices from adult sham-operated rats revealed normal passive and active intrinsic membrane properties and normal stimulus-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively). Regular spiking neurons recorded in rat dysplastic cortex showed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relationship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of multiphasic burst discharges, which coincided with extracellular field potentials and lasted 150-800 ms. These epileptiform responses could be recorded at membrane potentials between -50 and -110 mV and were blocked by -2-amino-5-phosphonovaleric acid (APV), indicating the involvement of N-methyl--aspartate (NMDA) receptors. Isolated NMDA-mediated and APV-sensitive EPSPs could be recorded at membrane potentials negative to -70 mV, suggesting that NMDA receptors are activated at relatively negative membrane potentials. In comparison with the controls, polysynaptic IPSPs mediated by the gamma-aminobutyric acid (GABA) type A and B receptor were either absent or reduced in peak conductance in microgyric cortex by 27% (P < 0.05) and 17%, respectively. However, monosynaptic IPSPs recorded in the presence of ionotropic glutamate receptor antagonists revealed a similar efficacy in NMD and control cortex, indicating that GABAergic neurons in microgyric cortex get a weaker excitatory input. Our data indicate that the expression of epileptiform activity in NMD-affected cortex rather results from an imbalance between excitatory and inhibitory synaptic transmission than from alterations in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor-mediated excitation in pyramidal neurons and a concurrent decrease of glutamatergic input onto inhibitory interneurons.

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“…4), suggesting that the effect of perampanel is specific on interhemispherically 358 propagated neural activity. This finding is in close agreement with intrahemispheric and 359 interhemispheric spread of epileptiform activity in rodent cortical slices that was not 360 influenced by application of the NMDA receptor antagonist D-2-amino-5-361 phosphonovaleric acid (D-APV), but blocked by the AMPA receptor antagonist 6-362 cyano-7-nitroquinoxaline-2,3-dione (CNQX) (Alefeld et al 1998;Telfeian and Connors 363 1999). The P70 has not shown reactivity to any other of the so far tested drugs (positive 364 allosteric modulators at the GABAA receptor, alpha-5 GABAA receptor antagonist, 365 GABAB receptor agonist, voltage-gated sodium channel blockers, NMDA receptor 366 antagonist, L-VGCC blocker) (Premoli et al 2014;Darmani et al 2016;Premoli et al 367 2017;Premoli et al 2018).…”

Section: P70 Modulation By Perampanel 353supporting

confidence: 60%

TMS-EEG signatures of glutamatergic neurotransmission in human cortex

Koenig

Belardinelli

Chen

et al. 2019

Preprint

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23Neuronal activity in the brain is regulated by an excitation-inhibition balance. Glutamate 24 is the main excitatory neurotransmitter. Transcranial magnetic stimulation (TMS) 25 evoked electroencephalographic (EEG) potentials (TEPs) represent a novel way to 26 quantify pharmacological effects on neuronal activity in the human cortex. Here we 27tested TEPs under the influence of a single oral dose of two anti-glutamatergic drugs, 28 perampanel, an AMPA-receptor antagonist, and dextromethorphan, an NMDA-29 receptor antagonist, and nimodipine, an L-type voltage-gated calcium channel blocker 30 in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled, 31 crossover design. Single-pulse TMS was delivered to the left motor cortex and TEPs 32 were obtained pre-and post-drug intake. Dextromethorphan specifically increased the 33 amplitude of the N45, a negative potential around 45 ms after the TMS pulse, while 34 perampanel reduced the P70 amplitude in the non-stimulated hemisphere. Nimodipine 35 and placebo had no effect on TEPs. These data extend previous pharmaco-TMS-EEG 36 studies by demonstrating that the N45 is regulated by a balance of GABAAergic 37 inhibition and NMDA-receptor-mediated glutamatergic excitation. In contrast, AMPA-38 receptor-mediated glutamatergic neurotransmission contributes to 39 interhemispherically propagated activity reflected in the P70. These data are important 40 to understand the physiology of TEPs as markers of excitability and propagated activity 41 in the human cortex in health and disease. 42 3 Introduction 43

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Pattern and Pharmacology of Propagating Epileptiform Activity in Mouse Cerebral Cortex

Cited by 27 publications

References 38 publications

Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings

Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings

Characterization of Neuronal Migration Disorders in Neocortical Structures. II. Intracellular In Vitro Recordings

TMS-EEG signatures of glutamatergic neurotransmission in human cortex

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