Gene expression in the epileptic (EL) mouse hippocampus.

The neuropathology of hippocampal seizure foci in human temporal lobe epilepsy (TLE) and several animal models of epilepsy reveal extensive neuronal loss along with astrocyte and microglial activation. Studies of these models have advanced hypotheses that propose both pathological changes are essential for seizure generation. However, some seizure foci in human TLE show an extreme loss of neurons in all hippocampal fields, giving weight to hypotheses that favor neuroglia as major players.

Periventricular White Matter Alterations From Explosive Blast in a Large Animal Model: Mild Traumatic Brain Injury or "Subconcussive" Injury?

The neuropathology of mild traumatic brain injury in humans resulting from exposure to explosive blast is poorly understood as this condition is rarely fatal. A large animal model may better reflect the injury patterns in humans. We investigated the effect of explosive blasts on the constrained head minimizing the effects of whole head motion.

Human and rodent temporal lobe epilepsy is characterized by changes in O-GlcNAc homeostasis that can be reversed to dampen epileptiform activity.

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-β-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that is derived from and closely associated with metabolic substrates. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal, respectively, of the O-GlcNAc modification.

Neuronal and glial changes in the brain resulting from explosive blast in an experimental model.

Mild traumatic brain injury (mTBI) is the signature injury in warfighters exposed to explosive blasts. The pathology underlying mTBI is poorly understood, as this condition is rarely fatal and thus postmortem brains are difficult to obtain for neuropathological studies. Here we report on studies of an experimental model with a gyrencephalic brain that is exposed to single and multiple explosive blast pressure waves.

Metabolic changes in early poststatus epilepticus measured by MR spectroscopy in rats.

There is little experimental in vivo data on how differences in seizure duration in experimental status epilepticus influence metabolic injury. This is of interest given that in humans, status duration is a factor that influences the probability of subsequent development of epilepsy. This question is studied using 7-T magnetic resonance (MR) spectroscopy, T2 relaxometry in the incremented kainate rodent model of temporal lobe epilepsy, using two durations of status epilepticus, 1.

Neuropathology of traumatic brain injury: comparison of penetrating, nonpenetrating direct impact and explosive blast etiologies.

The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood. The authors review and compare the known neuropathology in humans with severe, moderate, and mild TBI (mTBI) from nonpenetrating closed head injury (CHI) from blunt impacts and explosive blasts, as well as penetrating head injury (PHI). Penetrating head injury and CHI that are moderate to severe are more likely than mTBI to cause gross disruption of the cerebral vasculature.

Concussive brain injury from explosive blast.

Objective: Explosive blast mild traumatic brain injury (mTBI) is associated with a variety of symptoms including memory impairment and posttraumatic stress disorder (PTSD). Explosive shock waves can cause hippocampal injury in a large animal model. We recently reported a method for detecting brain injury in soldiers with explosive blast mTBI using magnetic resonance spectroscopic imaging (MRSI).

MRSI of the medial temporal lobe at 7 T in explosive blast mild traumatic brain injury.

Purpose: Up to 19% of veterans returning from the wars in Iraq and Afghanistan have a history of mild traumatic brain injury with 70% associated with blast exposure. Tragically, 20-50% of this group reports persistent symptoms, including memory loss. Unfortunately, routine clinical imaging is typically normal, making diagnosis and clinical management difficult.

Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy.

Purpose: Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE). Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear.

Glia and epilepsy: excitability and inflammation.

Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms.

Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy.

Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.

Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus.

Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder.

Neurological diseases as primary gliopathies: a reassessment of neurocentrism.

Diseases of the human brain are almost universally attributed to malfunction or loss of nerve cells. However, a considerable amount of work has, during the last decade, expanded our view on the role of astrocytes in CNS (central nervous system), and this analysis suggests that astrocytes contribute to both initiation and propagation of many (if not all) neurological diseases. Astrocytes provide metabolic and trophic support to neurons and oligodendrocytes.

Characteristics of an explosive blast-induced brain injury in an experimental model.

Mild traumatic brain injury resulting from exposure to an explosive blast is associated with significant neurobehavioral outcomes in soldiers. Little is known about the neuropathologic consequences of such an insult to the human brain. This study is an attempt to understand the effects of an explosive blast in a large animal gyrencephalic brain blast injury model.

Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus.

Monocarboxylate transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood-brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n=15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n=13) and neurologically normal autopsy subjects (n=8).

Astrocytes and epilepsy.

Astrocytes form a significant constituent of seizure foci in the human brain. For a long time it was believed that astrocytes play a significant role in the causation of seizures. With the increase in our understanding of the unique biology of these cells, their precise role in seizure foci is receiving renewed attention.

Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats.

An excess of extracellular glutamate in the hippocampus has been linked to the generation of recurrent seizures and brain pathology in patients with medically intractable mesial temporal lobe epilepsy (MTLE). However, the mechanism which results in glutamate excess in MTLE remains unknown. We recently reported that the glutamate-metabolizing enzyme glutamine synthetase is deficient in the hippocampus in patients with MTLE, and we postulated that this deficiency is critically involved in the pathophysiology of the disease.

Glutamate and astrocytes--key players in human mesial temporal lobe epilepsy?

Approximately one-third of all patients with epilepsy continue to suffer from seizures even after appropriate treatment with antiepileptic drugs. Medically refractory epilepsies are associated with considerable morbidity and mortality, and more efficacious therapies against these disorders are clearly needed. However, the discovery of better therapies has been lagging due to an incomplete understanding of the mechanisms underlying the development of epilepsy (epileptogensis) and seizures (ictogenesis) in humans.

Gene expression in temporal lobe epilepsy is consistent with increased release of glutamate by astrocytes.

Patients with temporal lobe epilepsy (TLE) often have a shrunken hippocampus that is known to be the location in which seizures originate. The role of the sclerotic hippocampus in the causation and maintenance of seizures in temporal lobe epilepsy (TLE) has remained incompletely understood despite extensive neuropathological investigations of this substrate. To gain new insights and develop new testable hypotheses on the role of sclerosis in the pathophysiology of TLE, the differential gene expression profile was studied.

Increased expression of phosphate-activated glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy.

Patients with mesial temporal lobe epilepsy (MTLE) have increased basal concentrations of extracellular glutamate in the epileptogenic versus the non-epileptogenic hippocampus. Such elevated glutamate levels have been proposed to underlie the initiation and maintenance of recurrent seizures, and a key question is what causes the elevation of glutamate in MTLE. Here, we explore the possibility that neurons in the hippocampal formation contain higher levels of the glutamate synthesizing enzyme phosphate-activated glutaminase (PAG) in patients with MTLE versus patients with other forms of temporal lobe epilepsy (non-MTLE).

GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus.

The gamma amino butyric acid (GABA) transporters GAT-1 and GAT-3 were localized by immunohistochemistry in hippocampi removed for the control of medically intractable temporal lobe epilepsy (TLE). The study aimed to determine the relationship of GABA transporter expression to known patterns of hippocampal hyperexcitability and extracellular GABA levels. GAT-1 was localized in axon terminals and small neuronal cell bodies, and in non-sclerotic hippocampi was strongly expressed throughout all regions of the hippocampal formation.

New facets of the neuropathology and molecular profile of human temporal lobe epilepsy.

This review summarizes the salient features of the anatomical and molecular neuropathology of the hippocampus from patients with intractable temporal lobe epilepsy (TLE). It argues that sclerotic hippocampus is essential for seizure expression and that sclerosis is not a consequence of seizures, but is related to the epileptogenicity of the seizure focus. While neurons in sclerotic hippocampus may contribute to hippocampal hyperexcitability, this role is perhaps less important than that of the astrocytes.

Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus.

An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE.

Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy.

The hippocampus of patients with mesial temporal lobe epilepsy is often hardened and shrunken, a condition known as sclerosis. Magnetic resonance imaging reveals an increase in the T2-weighted signal, while diffusion weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicating increased water content. As water transport appears to be coupled to K+ clearance and neuronal excitability [4], the molecular basis of the perturbed water homeostasis in the sclerotic hippocampus was explored.