Electrophysiological properties of human hypothalamic hamartomas

Abstract

The hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures, which are usually refractory to medical therapy. The mechanisms of epileptogenesis operative in this subcortical lesion are unknown. In this study, we used standard patch-clamp electrophysiological techniques combined with histochemical approaches to study individual cells from human HH tissue immediately after surgical resection. More than 90% of dissociated HH cells were small (6-9 microm soma) and exhibited immunoreactivity to the neuronal marker NeuN, and to glutamic acid decarboxylase, but not to glial fibrillary acidic protein. Under current-clamp, whole-cell recordings in single dissociated cells or in intact HH slices demonstrated typical neuronal responses to depolarizing and hyperpolarizing current injection. In some cases, HH cells exhibited a "sag-like" membrane potential change during membrane hyperpolarization. Interestingly, most HH cells exhibited robust, spontaneous "pacemaker-like" action potential firing. Under voltage-clamp, dissociated HH cells exhibited functional tetrodotoxin (TTX)-sensitive Na(+) and tetraethylammonium-sensitive K(+) currents. Both GABA and glutamate evoked whole-cell currents, with GABA exhibiting a peak current amplitude 10-fold greater than glutamate. These findings suggest that human HH tissues, associated with gelastic seizures, contained predominantly small GABAergic inhibitory neurons that exhibited intrinsic "pacemaker-like" behavior.

Radiosurgery for hypothalamic hamartomas

“…4,9,11,12,16,21,22,26,35,45 The epileptogenic activity of HHs has been recently demonstrated at the cellular level: detailed electrophysiological analysis of slices taken from surgical specimens showed the predominance of small GABAergic inhibitory neurons exhibiting an intrinsic "pacemaker-like" behavior. 54 The concept that surgical intervention should mainly target the HH was not easy to accept. The path toward acceptance was paved by failed procedures such as temporal or frontal lobectomies, parietal corticectomies, or corpus callosotomies.…”

“…Electrophysiological characterization of HH neurons has shown that an intrinsic epileptogenic activity is present. 4,5,21,22,32,54 Epileptogenic HH are invariably attached to one or both of the mammillary bodies. 15 Spread of the epileptogenic activity and induction of generalized seizures require access to the thalamocortical loops via the mammillothalamic tract.…”

Surgical management of hypothalamic hamartomas in patients with gelastic epilepsy

“…31,32,47 Lastly, pacemaker-like activity can be found within clusters of cells in resected hamartomas, supporting the notion that epileptic properties are indeed intrinsic to the hamartomas themselves. 60 …”

Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics

“…41,64 In addition to a continuous pacemaker-like firing pattern, these small neurons, which express GABA A receptors and are probably inhibitory interneurons, also exhibit irregular spiking and bursting firing patterns. 118 In contrast, spontaneous activity was not detected in large HH neurons. 41 Ultrastructural studies have also demonstrated that these 2 neuronal populations have distinct morphological and synaptic profiles.…”