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.
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ABSTRACT: Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways on the other. It exerts its action through a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated previously in a broad spectrum of acute and chronic neurodegenerative diseases. In this review, we discuss existing data on the role of glutamate as a growth factor for neoplastic cells, the expression of glutamate receptors in various types of benign and malignant neoplasms, and the potential roles that GluRs play in cancer development and progression along with their clinical significance. We conclude that glutamate-related receptors and their signaling pathways may provide novel therapeutic opportunities for a variety of malignant human diseases.Journal of Neural Transmission 03/2014; 121(8). DOI:10.1007/s00702-014-1182-6 · 2.87 Impact Factor
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ABSTRACT: Objective: Human hypothalamic hamartomas (HH) are intrinsically epileptogenic and are associated with treatment-resistant gelastic seizures. The basic cellular mechanisms responsible for seizure onset within HH are unknown. We used intra-operative microwire recordings of single neuron activity to measure the spontaneous firing rate of neurons and the degree of functional connection between neurons within the tumor.Technique: Fourteen patients underwent transventricular endoscopic resection of HH for treatment-resistant epilepsy. Prior to surgical resection, single neuron recordings from bundled microwires (total of nine contacts) were obtained from HH tissue. Spontaneous activity was recorded for two or three 5-min epochs under steady-state general anesthesia. Off-line analysis included cluster analysis of single unit activity and probability analysis of firing relationships between pairs of neurons.Results: Altogether, 222 neurons were identified (mean 6 neurons per recording epoch). Cluster analysis of single neuron firing utilizing a mixture of Gaussians model identified two distinct populations on the basis of firing rate (median firing frequency 0.6 versus 15.0 spikes per second; p < 10−5). Cluster analysis identified three populations determined by levels of burst firing (median burst indices of 0.015, 0.18, and 0.39; p < 10−15). Unbiased analysis of spontaneous single unit behavior showed that 51% of all possible neuron pairs within each recording epoch had a significant level of firing synchrony (p < 10−15). The subgroup of neurons with higher median firing frequencies was more likely to demonstrate synchronous firing (p < 10−7).Conclusion: Hypothalamic hamartoma tissue in vivo contains neurons which fire spontaneously. The activity of single neurons is diverse but distributes into at least two electrophysiological phenoytpes. Functional linkage between single neurons suggests that HH neurons exist within local networks that may contribute to ictogenesis.Frontiers in Neurology 12/2013; 4:210. DOI:10.3389/fneur.2013.00210
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ABSTRACT: Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.Neurobiology of Disease 10/2013; 62. DOI:10.1016/j.nbd.2013.10.001 · 5.20 Impact Factor