Anomalous Inhibitory Circuits in Cortical Tubers of Human Tuberous Sclerosis Complex Associated With Refractory Epilepsy: Aberrant Expression of Parvalbumin and Calbindin-D28k in Dysplastic Cortex

Abstract

Damage or loss of inhibitory cortical gamma-aminobutyric acid (GABA)ergic interneurons is associated with impaired inhibitory control of neocortical pyramidal cells, leading to hyperexcitability and epileptogenesis. The calcium binding proteins parvalbumin and calbindin-D(28k) are expressed in subpopulations of GABAergic local circuit neurons in the neocortex and can serve as neuronotypic markers. Parvalbumin and calbindin-D(28k) facilitate the neuron's ability to sustain firing and provide neuroprotection. The goal of this study was to assess the hitherto unknown status of inhibitory interneurons in cortical tubers of human tuberous sclerosis complex. Surgically excised cortical tubers from three patients with tuberous sclerosis complex were evaluated immunohistochemically with antibodies to parvalbumin and calbindin-D(28k). Cortical specimens from young patients with intractable seizures, including microdysgenesis (n = 3), postischemic cortical scarring (n = 1), porencephaly (n = 1), postictal gliosis (n = 3), and low-grade neuronal or glial tumors (n = 5), were also examined for comparison. In cortical tubers, calcium binding protein immunoreactivities (calbindin-D(28k) > parvalbumin) were present in medium- or large-size dysplastic neurons, whereas giant or ballooned cells were parvalbumin or calbindin-D(28k) negative. In microdysgenesis, a nearly normal number of parvalbumin-positive neurons and a decreased number of calbindin-D(28k)-positive neurons were present. In peritumoral but more so in gliotic cortex, a coordinate decrease of parvalbumin and calbindin-D(28k) immunoreactivities was present. Our findings indicate that the expression of parvalbumin or calbindin-D(28k) by subpopulations of dysplastic neurons in cortical tubers is aberrant and denotes dysfunctional inhibitory circuits inept for excitoprotection.

Imbalance of interneuron distribution between neocortex and basal ganglia: Consideration of epileptogenesis of focal cortical dysplasia

“…In previous studies, the number of inhibitory neurons in patients with intractable epilepsy and mammalian models shows a variable aberrant pattern, such as a decreased or increased number of GABAergic interneurons [3,22]. Interestingly, approximately 35% of neocortical interneurons in the human brain originate in the subventricular zone [1].…”

“…It is thought that epilepsy results from molecular changes in glutamate and GABA receptors of aberrant neurons, causing a functional imbalance characterized by increased excitation and decreased inhibition [2,3]. Damage or loss of inhibitory GABAergic interneuron is associated with impaired inhibitory control of cortical pyramidal neurons, leading to hyperexcitability and epileptogenesis [3,4].…”

“…Damage or loss of inhibitory GABAergic interneuron is associated with impaired inhibitory control of cortical pyramidal neurons, leading to hyperexcitability and epileptogenesis [3,4]. Malformations of cortical development (MCDs) are increasingly recognized as an underlying pathology in children with medically intractable epilepsy [5].…”

Epilepsy Mechanisms in Neurocutaneous Disorders: Tuberous Sclerosis Complex, Neurofibromatosis Type 1, and Sturge–Weber Syndrome

“…In cortical specimens from patients with TSC, the number of GABAergic interneurons is decreased, consistent with diminished and aberrant local inhibition (60). Excessive depolarizing GABA responses in tuberal neurons were blocked by bumetanide, a compound that inhibits the ion transporter sodium-potassium-chloride cotransporter 1 (NKCC1) (61, 62).…”

Management of epilepsy in tuberous sclerosis complex

“…In a recent immunohistochemical study of surgically resected cortical tubers from three TSC patients, aberrant expression of parvalbumin and calbindin-D28k was observed in dyplastic neurons, demonstrating that in cortical tubers anomalous inhibitory circuits are associated with refractory epilepsy [40]. Experimental data suggest that interneuron-deficient mice display enhanced seizure susceptibility due to the diminished inhibitory control of the excitatory neurotransmitter system [41].…”