A Cholinergic Synaptically Triggered Event Participates in the Generation of Persistent Activity Necessary for Eye Fixation

An exciting topic regarding integrative properties of the nervous system is how transient motor commands or brief sensory stimuli are able to evoke persistent neuronal changes, mainly as a sustained, tonic action potential firing. A persisting firing seems to be necessary for postural maintenance after a previous movement. We have studied in vitro and in vivo the generation of the persistent neuronal activity responsible for eye fixation after spontaneous eye movements. Rat sagittal brainstem slices were used for the intracellular recording of prepositus hypoglossi (PH) neurons and their synaptic activation from nearby paramedian pontine reticular formation (PPRF) neurons. Single electrical pulses applied to the PPRF showed a monosynaptic glutamatergic projection on PH neurons, acting on AMPA-kainate receptors. Train stimulation of the PPRF area evoked a sustained depolarization of PH neurons exceeding (by hundreds of milliseconds) stimulus duration. Both duration and amplitude of this sustained depolarization were linearly related to train frequency. The train-evoked sustained depolarization was the result of interaction between glutamatergic excitatory burst neurons and cholinergic mesopontine reticular fibers projecting onto PH neurons, because it was prevented by slice superfusion with cholinergic antagonists and mimicked by cholinergic agonists. As expected, microinjections of cholinergic antagonists in the PH nucleus of alert behaving cats evoked a gaze-holding deficit consisting of a re-centering drift of the eye after each saccade. These findings suggest that a slow, cholinergic, synaptically triggered event participates in the generation of persistent activity characteristic of PH neurons carrying eye position signals.Unión Europea Grants BI04-CT98-0546España, Ministerio de Ciencia PB98-0011, BFI2000-00936, BFI2000-1190, y BFI2002-0137

Detection of pantothenic acid-immunoreactive neurons in the rat lateral septal nucleus by a newly developed antibody

Introduction. The available immunohistochemical techniques have documented restricted distribution of vitamins in the mammalian brain. The aim of the study was to develop a highly specific antiserum directed against pantothenic acid to explore the presence of this vitamin in the mammalian brain. Material and methods. According to ELISA tests, the anti-pantothenic acid antiserum used showed a good affinity (10–8 M) and specificity. The antiserum was raised in rabbits. Using an indirect immunoperoxidase technique, the mapping of pantothenic acid-immunoreactive structures was carried out in the rat brain. Results. Pantothenic acid-immunoreactive perikarya were exclusively found in the intermediate part of the lateral septal nucleus. These cells were generally small, round, fusiform or pyramidal and showed 2–3 long (50–100 μm) immunoreactive dendrites. Any immunoreactive axons containing pantothenic acid were detected. Conclusions. The very restricted anatomical distribution of the pantothenic acid suggests that this vitamin could be involved in some specific neurophysiological mechanisms

GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, brain atrophy due to neuronal and synapse loss, and formation of two pathological lesions: extracellular amyloid plaques, composed largely of amyloid-beta peptide (Aβ), and neurofibrillary tangles formed by intracellular aggregates of hyperphosphorylated tau protein. Lesions mainly accumulate in brain regions that modulate cognitive functions such as the hippocampus, septum or amygdala. These brain structures have dense reciprocal glutamatergic, cholinergic, and GABAergic connections and their relationships directly affect learning and memory processes, so they have been proposed as highly susceptible regions to suffer damage by Aβ during AD course. Last findings support the emerging concept that soluble Aβ peptides, inducing an initial stage of synaptic dysfunction which probably starts 20–30 years before the clinical onset of AD, can perturb the excitatory–inhibitory balance of neural circuitries. In turn, neurotransmission imbalance will result in altered network activity that might be responsible of cognitive deficits in AD. Therefore, Aβ interactions on neurotransmission systems in memory-related brain regions such as amygdaloid complex, medial septum or hippocampus are critical in cognitive functions and appear as a pivotal target for drug design to improve learning and dysfunctions that manifest with age. Since treatments based on glutamatergic and cholinergic pharmacology in AD have shown limited success, therapies combining modulators of different neurotransmission systems including recent findings regarding the GABAergic system, emerge as a more useful tool for the treatment, and overall prevention, of this dementia. In this review, focused on inhibitory systems, we will analyze pharmacological strategies to compensate neurotransmission imbalance that might be considered as potential therapeutic interventions in AD

Overexpression of kynurenic acid and 3-hydroxyanthranilic acid after rat traumatic brain injury

[EN]Using an immunohistochemical technique, we have studied the distribution of kynuneric acid (KYNA) and 3-hydroxyanthranilic acid (3-HAA) in a rat brain injury model (trauma). The study was carried out inducing a cerebral ablation of the frontal motor cortex. Two mouse monoclonal specific antibodies previously developed by our group directed against KYNA and 3-HAA were used. In control animals (sham-operated), the expression of both KYNA and 3-HAA was not observed. In animals in which the ablation was performed, the highest number of immunoreactive cells containing KYNA or 3-HAA was observed in the region surrounding the lesion and the number of these cells decreased moving away from the lesion. KYNA and 3-HAA were also observed in the white matter (ipsilateral side) located close to the injured region and in some cells placed in the white matter of the contralateral side. The distribution of KYNA and 3-HAA perfectly matched with the peripheral injured regions. The results found were identical independently of the perfusion date of animals (17, 30 or 54 days after brain injury). For the first time, the presence of KYNA and 3-HAA has been described in a rat trauma model

Trasplantes amigdalares embrionarios en ratas adultas con lesiones de la corteza motora: análisis molecular y electrofisiológico

Transplants of embryonic nervous tissue ameliorate motor deficits induced by motor cortex lesions in adult animals. Restoration of lost brain functions has been recently shown in grafts of homotopic cortical origin, to be associated with a functional integration of the transplant after development of reciprocal host-graft connections. Nevertheless little is known about physiological properties or gene expression profiles of cortical implants with functional restorative capacity but no cortical origin. In this study, we show molecular and electrophysiological evidence supporting the functional development and integration of heterotopic transplants of embryonic amygdalar tissue placed into pre-lesioned motor cortex of adult rats. Grafts were analyzed 3 months post-transplantation

Neurons of the Dentate Molecular Layer in the Rabbit Hippocampus

The molecular layer of the dentate gyrus appears as the main entrance gate for information into the hippocampus, i.e., where the perforant path axons from the entorhinal cortex synapse onto the spines and dendrites of granule cells. A few dispersed neuronal somata appear intermingled in between and probably control the flow of information in this area. In rabbits, the number of neurons in the molecular layer increases in the first week of postnatal life and then stabilizes to appear permanent and heterogeneous over the individuals’ life span, including old animals. By means of Golgi impregnations, NADPH histochemistry, immunocytochemical stainings and intracellular labelings (lucifer yellow and biocytin injections), eight neuronal morphological types have been detected in the molecular layer of developing adult and old rabbits. Six of them appear as interneurons displaying smooth dendrites and GABA immunoreactivity: those here called as globoid, vertical, small horizontal, large horizontal, inverted pyramidal and polymorphic. Additionally there are two GABA negative types: the sarmentous and ectopic granular neurons. The distribution of the somata and dendritic trees of these neurons shows preferences for a definite sublayer of the molecular layer: small horizontal, sarmentous and inverted pyramidal neurons are preferably found in the outer third of the molecular layer; vertical, globoid and polymorph neurons locate the intermediate third, while large horizontal and ectopic granular neurons occupy the inner third or the juxtagranular molecular layer. Our results reveal substantial differences in the morphology and electrophysiological behaviour between each neuronal archetype in the dentate molecular layer, allowing us to propose a new classification for this neural population

Major Neuroanatomical And Neurochemical Substrates Involved In Primary Headaches

Neuroanatomical structures involved in head pain are primarily the sensory distribution of four cranial nerves: the trigeminal-and to a lesser extent, facial, glossopharyngeal, and vagus-as well as the terminations of the upper three cervical nerves.In addition, various pain sensitive cranial structures including the scalp and its blood supply, the head and neck muscles, intracranial and meningeal arteries, and dura mater including the venous sinuses are the major anatomical substrates of various types of headaches. Although brain tumors, different types of hemorrhage, hypertension, and meningitis may present as a headache, the migraine, cluster, and tension headaches are the three major types of primary headaches. Current opinion suggests a primary central nervous system activation may initiate a migraine. Several triggering factors such as disturbances of brain oxygenation and metabolism, alterations in the serotonin levels, low levels of brain tissue magnesium, altered transport of ions across the cell membrane, abnormal mitochondrial energy metabolism, and genetic abnormalities including mutations of the P/Q type calcium channel gene, Na+/K+ pump ATP1A2, or sodium channel Nav1.1 mutations have been linked to the pathogenesis of migraines. Patients with mutations in the calcium channel gene are more sensitive to environmental factors, which results in a wave of cortical spreading depression in the patient after the attack is initiated.Moreover, several recent clinical and diagnostic studies indicate a dysfunction of the brainstem periaqueductal gray matter during migraine, or initiation of migraine by activation of the brainstem including the dorsal rostral and midline pons. Consistent with this, an active locus in the posterior hypothalamus has been implicated in cluster headache (CH). The headache phase involves the activation of the trigeminovascular system and possibly dilatation of the cranial blood vessels presumably mediated by the release of vasoactive substances and neuropeptides including the calcitonin gene-related peptide (CGRP). Increased serum CGRP levels were detected during migraine and CH. In addition, in CH, there is a release of parasympathetic peptide, vasoactive intestinal peptide. Currently, inhibiting the release of vasoactive substances and neuropeptides including the CGRP or nitric oxide, or blocking their receptors in the neuroanatomical substrates of head pain is a major focus in treatment of headaches. © 2010 by Nova Science Publishers, Inc. All rights reserved

Neuropeptides And Other Chemical Mediators, And The Role Of Antiinflammatory Drugs In Primary Headaches

Primary headaches including the migraine, cluster, and tension headaches are common neurological disorders which cause pain and disability to the patients. The pathomechanism of migraine is not very well understood however, current clinical findings indicate a possible primary brain disorder due to activation of the brain and brainstem as triggers for migraine. The headache phase of migraine may be due to activation of the peripheral nerves including the trigeminal nerve and others innervating the cranial blood vessels and release of vasoactive substances including the calcitonin generelated peptides (CGRP), possibly leading to vasodilation and brainstem activation. Several of our studies in an experimental model of pain using electrical stimulation of the trigeminal ganglion in rats focused on various neuropeptides release from the peripheral and central trigeminal nerve terminals, however, clinically only the CGRP in migraine and CGRP and vasoactive intestinal peptide (VIP) in cluster headache were found in patient\u27s blood. Although several drugs are used in the treatment of migraine, the non-steroid anti-inflammatory drugs (NSAIDs) and the triptan family of drugs are the first choice drugs recommended for the treatment of acute migraine headache. Although clinically very few studies detected other vasoactive/inflammatory molecules in the blood of migraine patients, sensitization of peripheral axons can involve many inflammatory mediators affecting the peripheral tissue substrates of pain. Moreover, central sensitization in the trigeminal nucleus can also contribute to additional pain responses. This article reviews neuropeptides and other molecules involved in primary headaches and major drugs proposed for their treatment in recent years. © 2010 Bentham Science Publishers Ltd

Amyloid-β(25-35) Modulates the Expression of GirK and KCNQ Channel Genes in the Hippocampus.

During early stages of Alzheimer's disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD

El amiloide-? induce una disfunción sináptica a través de los canales de potasio rectificadores hacia adentro activados por la proteína G en la sinapsis del hipocampo fimbria-CA3

Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-? (A?) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of A? on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABAA antagonists whereas the late IPSP was removed by GABAB antagonists. A? perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. A? action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all A? effects previously described