Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

Abstract

Summary Purpose: A disturbed balance between excitatory and inhibitory neurotransmission underlies epileptic activity, although reports concerning neurotransmitter systems involved remain controversial. Methods: We quantified densities of 15 receptors in neocortical biopsies from patients with pharmacoresistant focal temporal lobe epilepsy and autopsy controls, and searched for correlations between density alterations and clinical factors or the occurrence of spontaneous synaptic potentials in vitro. Key Findings: α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), kainate, N‐methyl‐d‐aspartate (NMDA), peripheral benzodiazepine, muscarinic (M)1, M2, nicotinic, α1, α2h, serotonin (5‐HT)1A, and adenosine (A)1 receptor densities were significantly altered in biopsies. The epileptic cohort was subdivided based on clinical (febrile seizures, hippocampal sclerosis, neocortical pathologies, surgery outcome) or electrophysiologic (spontaneous field potentials) criteria, resulting in different patterns of significantly altered receptor types when comparing a given epileptic group with controls. Only AMPA, kainate, M2, and 5‐HT1A receptors were always significantly altered. γ‐Aminobutyric acid (GABA)A, GABAB, and 5‐HT2 receptor alterations were never significant. Correlation patterns between receptor alterations and illness duration or seizure frequency varied depending on whether the epileptic cohort was considered as a whole or subdivided. Significance: Neocortical temporal lobe epilepsy is associated with a generalized receptor imbalance resulting in a net potentiation of excitatory neurotransmission. Peripheral benzodiazepine receptor alterations highlight that astrocytes are also impaired by seizure activity.

Perampanel, an Antagonist of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors, for the Treatment of Epilepsy: Studies in Human Epileptic Brain and Nonepileptic Brain and in Rodent Models

“…AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors regulate fast excitatory neurotransmission in the mammalian nervous system and have been a target of AED discovery and development for many years. Additionally, data from genetic studies (Lerche et al, 2013) as well as AMPA receptor upregulation in brains from epileptic patients (Palomero-Gallagher et al, 2012) have added additional rationale for targeting AMPA receptors in the control of epilepsy.…”

“…The hypothesis was tested with novel electrophysiologic techniques to study the sensitivity to perampanel of AMPA receptors from different brain areas of both rats and humans. In addition, because epileptic brain tissue has shown changes in AMPA receptor density (Brines et al, 1997;Palomero-Gallagher et al, 2012), we also evaluated the effects of perampanel in human epileptic brains.…”

5‐hydroxytryptamine1A receptor density in the hippocampus of patients with temporal lobe epilepsy is associated with disease duration

“… analyzed the amygdala of an etiologically heterogeneous sample of patients with TLE and found a lower density (downregulation) of 5‐HT1AR. The same group observed higher 5‐HT1AR density when analyzing the middle temporal gyrus of pharmacoresistant TLE in a similar sample. A possible reason for these contradictory results is the region analyzed.…”

“…Temporal lobe epilepsy caused by hippocampal sclerosis (HS) is the most common cause of pharmacoresistant focal epilepsy referred to surgery [14] and it represents an excellent model for neurophysiologic studies. However, there are few studies in human brain tissue that have evaluated the role of 5-HTRs in epileptogenesis [15][16][17]. Graebenitz et al [16] analyzed the amygdala of an etiologically heterogeneous sample of patients with TLE and found a lower density (downregulation) of 5-HT1AR.…”

Malformations of Cortical Development and Neocortical Focus

“…Focal defects in cortical organization often involve deeper cortical neurons and the white matter (Rossini et al, 2011), supporting the hypothesis that surviving subplate neurons may be involved in the pathophysiology of some forms of human focal epilepsies. Quantitative receptor autoradiography in the neocortex of patients with focal epilepsy revealed a prominent and consistent increase in the density of AMPA receptor-binding sites, but no significant changes in NMDA or GABA-A receptors (Palomero-Gallagher et al, 2012;Zilles, Qü, K€ ohling, & Speckmann, 1999).…”