Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study.

Purpose: It remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease.

Dopamine modulation of excitatory currents in the striatum is dictated by the expression of D1 or D2 receptors and modified by endocannabinoids.

Striatal medium-sized spiny neurons (MSSNs) receive glutamatergic inputs modulated presynaptically and postsynaptically by dopamine. Mice expressing the gene for enhanced green fluorescent protein as a reporter gene to identify MSSNs containing D1 or D2 receptor subtypes were used to examine dopamine modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices and postsynaptic N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents in acutely isolated cells. The results demonstrated dopamine receptor-specific modulation of sEPSCs.

Luteinizing hormone provides a causal mechanism for mercury associated disease.

Previous studies have demonstrated that the pituitary is a main target for inorganic mercury (I-Hg) deposition and accumulation within the brain. My recent study of the US population (1999-2006) has uncovered a significant, inverse relationship between chronic mercury exposure and levels of luteinizing hormone (LH). This association with LH signifies more than its presumed role as bioindicator for pituitary neurosecretion and function.

Targeted ablation and reorganization of the principal preplate neurons and their neuroblasts identified by golli promoter transgene expression in the neocortex of mice.

The present study delineates the cellular responses of dorsal pallium to targeted genetic ablation of the principal preplate neurons of the neocortex. Ganciclovir treatment during prenatal development (E11-E13; where E is embryonic day) of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene, linked to HSV-TK (herpes simplex virus-thymidine kinase), τ-eGFP (τ-enhanced green fluorescent protein) and lacZ (lacZ galactosidase) reporters] localized in preplate neurons. Morphogenetic fates of attacked neurons and neuroblasts, and their successors, were assessed by multiple labelling in time-series comparisons between ablated (HSV-TK+/0) and control (HSV-TK0/0) littermates.

Challenges in the surgical treatment of epilepsy patients with cortical dysplasia.

Cortical dysplasia (CD) is the most common malformation of cortical development in epilepsy surgery patients. Patients with mild Palmini type I CD represent about 50% of the surgical cases, and these lesions tend to occur most often in the temporal lobe, often associated with hippocampal sclerosis. By comparison, patients with severe type II CD present at younger ages, often with multilobar extratemporal lesions, and more aggressive seizures.

Assessment of chronic mercury exposure within the U.S. population, National Health and Nutrition Examination Survey, 1999–2006.

The purpose of this study was to assess chronic mercury exposure within the US population. Time trends were analyzed for blood inorganic mercury (I-Hg) levels in 6,174 women, ages 18-49, in the NHANES, 1999-2006 data sets. Multivariate logistic regression distinguished a significant, direct correlation within the US population between I-Hg detection and years since the start of the survey (OR = 1.

Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.

Previously, we identified progressive alterations in spontaneous EPSCs and IPSCs in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons from these mice displayed a lower frequency of EPSCs, and a population of cells exhibited an increased frequency of IPSCs beginning at approximately 40 d, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression.

Evidence for oxidative stress in the developing cerebellum of the rat after chronic mild carbon monoxide exposure (0.0025% in air).

Background: The present study was designed to test the hypothesis that chronic very mild prenatal carbon monoxide (CO) exposure (25 parts per million) subverts the normal development of the rat cerebellar cortex. Studies at this chronic low CO exposure over the earliest periods of mammalian development have not been performed to date. Pregnant rats were exposed chronically to CO from gestational day E5 to E20.

The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis.

Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease.

Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits and is caused by an abnormal expansion of the CAG tract in the huntingtin (htt) gene. In humans, mutated htt induces a preferential loss of medium spiny neurons in the striatum and, to a lesser extent, a loss of cortical neurons as the disease progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation.

Transcriptional regulation of neuronal differentiation: the epigenetic layer of complexity.

The transcriptional programs of neural progenitor cells change dynamically during neurogenesis, a process regulated by both intrinsic and extrinsic factors. Although many of the transcription factors required for neuronal differentiation have long been identified, we are only at the brink of understanding how epigenetic mechanisms influence transcriptional activity and the accessibility of transcription factors to bind consensus cis-elements. Herein, we delineate the chief epigenetic modifications and the machinery responsible for these alterations.

Activation of inflammatory response by a combination of growth factors in cuprizone-induced demyelinated brain leads to myelin repair.

In vivo remyelination promoted by a combination of four oligodendrocyte specific growth factors (GFs) in cuprizone-induced demyelinated mice brains was described recently by our group. Here we report activation of inflammatory response in mice brain following cuprizone-induced demyelination and its further enhancement immediately after injection of growth factors in vivo, while no significant inflammatory response was evident in GFs-injected normal brains. Cuprizone-induced demyelination was accompanied by increased expression of inflammatory cytokines, TNFalpha and IL-1beta, anti-inflammatory cytokines TGFbeta, IL-10 and increased levels of chemokines, CCL2, CCL5, and CXCL10, produced by resident microglia and astrocytes.

Pyramidal cell responses to gamma-aminobutyric acid differ in type I and type II cortical dysplasia.

Abnormalities in the gamma-aminobutyric acid (GABA)-ergic system could be responsible for seizures in cortical dysplasia (CD). We examined responses of pyramidal neurons to exogenous application of GABA, as well as alterations of GABAergic interneuron number and size in pediatric epilepsy surgery patients with non-CD, type I CD, and type II CD pathologies. We used the dissociated cell preparation for electrophysiology along with immunohistochemistry to identify number and size of GABAergic cells.

Vasoactive intestinal peptide is critical for circadian regulation of glucocorticoids.

Background/aims: Circadian control of behavior and physiology is a central characteristic of all living organisms. The master clock in mammals resides in the hypothalamus, where the suprachiasmatic nucleus (SCN) synchronizes daily rhythms. A variety of recent evidence indicates that the neuropeptide vasoactive intestinal peptide (VIP) is critical for normal functioning of the SCN.

Mice deficient in both pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide survive, but display growth retardation and sex-dependent early death.

Pituitary adenylyl cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two closely related neuropeptides exhibiting overlapping activities which have actions on almost every organ system of the body. To determine if these peptides exert essential but redundant functions, we interbred VIP- and PACAP-deficient mice to obtain VIP/PACAP double knockout (DKO) mice. DKO mice had normal birth weights and survived to weaning, but exhibited a dramatic postnatal growth rate reduction.

Neuronal coupling via connexin36 contributes to spontaneous synaptic currents of striatal medium-sized spiny neurons.

Gap junctions provide a means for electrotonic coupling between neurons, allowing for the generation of synchronous activity, an important contributor to learning and memory. Connexin36 (Cx36) is largely neuron specific and provides a target for genetic manipulation to determine the physiological relevance of neuronal coupling. Within the striatum, Cx36 is more specifically localized to the interneuronal population, which provides the main inhibitory input to the principal projection medium-sized spiny neurons.

Differential electrophysiological properties of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons.

The electrophysiological properties of distinct subpopulations of striatal medium-sized spiny neurons (MSSNs) were compared using enhanced green fluorescent protein as a reporter gene for identification of neurons expressing dopamine D1 and D2 receptor subtypes in mice. Whole-cell patch-clamp recordings in slices revealed that passive membrane properties were similar in D1 and D2 cells. All MSSNs displayed hyperpolarized resting membrane potentials but the threshold for firing action potentials was lower in D2 than in D1 neurons.

CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain.

The postnatal forebrain subventricular zone (SVZ) harbors stem cells that give rise to olfactory bulb interneurons throughout life. The identity of stem cells in the adult SVZ has been extensively debated. Although, ependymal cells were once suggested to have stem cell characteristics, subsequent studies have challenged the initial report and postulated that subependymal GFAP(+) cells were the stem cells.

Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP.

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immune-based diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis.

Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide.

Peripheral nerve injury models are used to investigate processes that can potentially be exploited in CNS injury. A consistent change that occurs in injured peripheral neurons is an induction in expression of pituitary adenylyl cyclase activating peptide (PACAP), a neuropeptide with putative neuroprotective and neuritogenic actions. PACAP-deficient mice were used here to investigate actions of endogenous PACAP after facial nerve injury.

Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice.

Hedgehog (Hh) proteins and cAMP-dependent protein kinase A (PKA) generally play opposing roles in developmental patterning events. Humans and mice heterozygous for mutations in the sonic hedgehog (Shh) receptor gene patched-1 (ptc1) have an increased incidence of certain types of cancer, including medulloblastoma (MB), a highly aggressive tumor of the cerebellum. Despite the importance of PKA in Hh signaling, little is known about how PKA activity is regulated in the context of Hh signaling, or the consequences of improper regulation.

Neurons or glia? Can SHP2 know it all?

Normal development of the nervous system relies on the spatially and temporally well-controlled differentiation of neurons and glia. Here, we discuss the intra- and extracellular molecular mechanisms that underlie the sequential genesis of neurons and glia, emphasizing recent studies describing the role of a signaling molecule, the tyrosine phosphatase SHP2, in normal brain development. Activation of SHP2 simultaneously enhances downstream activation of the MEK-ERK pathway, which subsequently promotes neurogenesis, while inhibiting the JAK-STAT pathway, which is critical for astroglial differentiation.

Immature neurons and GABA networks may contribute to epileptogenesis in pediatric cortical dysplasia.

Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors and the persistence of subplate-like neurons and undifferentiated cells. Because gamma-aminobutyric acid (GABA) is the main neurotransmitter in early cortical development, we hypothesized increased GABA receptor-mediated synaptic function in CD tissue. Infrared videomicroscopy and whole-cell patch clamp recordings were used to characterize the morphology and electrophysiological properties of immature and normal-appearing neurons in slices from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy in children (0.