- Sevilla, Andalucia, Spain
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Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully... more
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1– microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and p...
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Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a... more
Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1+microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.
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Background One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of... more
Background One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. Results Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster...
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Apomorphine is a dopamine receptor agonist that activates D-D dopamine receptors and that is used to treat Parkinson's disease (PD). However, the effect of apomorphine on non-motor activity has been poorly studied, and likewise, the... more
Apomorphine is a dopamine receptor agonist that activates D-D dopamine receptors and that is used to treat Parkinson's disease (PD). However, the effect of apomorphine on non-motor activity has been poorly studied, and likewise, the effects of dopaminergic activation in brain areas that do not fulfill motor functions are unclear. The aim of this study was to determine how dopamine receptor activation affects behavior, as well as plasticity, morphology, and oxidative stress in the hippocampus. Adult mice were chronically administered apomorphine (1 mg/kg for 15 days), and the effects on memory and learning, synaptic plasticity, dendritic length, inflammatory responses, and oxidative stress were evaluated. Apomorphine impaired learning and long-term memory in mice, as evaluated in the Morris water maze test. In addition, electrophysiological recording of field excitatory postsynaptic potentials (fEPSP) indicated that the long-term potentiation (LTP) of synaptic transmission in the...
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Glutamate is the most abundant excitatory neurotransmitter in the hippocampus where mediates its actions by activating glutamate receptors. The activation of these receptors is essential for the maintenance and dynamics of dendritic... more
Glutamate is the most abundant excitatory neurotransmitter in the hippocampus where mediates its actions by activating glutamate receptors. The activation of these receptors is essential for the maintenance and dynamics of dendritic spines and plasticity that correlate with learning and memory processes during neurodevelopment and adulthood. We studied in adults the effect of blocking ionotropic glutamate receptors (NMDAR, AMPAR, and KAR) functions at neonatal age (PD1-PD15) with their respective antagonists D-AP5, GYKI-53655 and UBP-302. We first evaluated memory using a new object recognition test in adults. Second, we evaluated the levels of glial fibrillary acidic protein, synaptophysin and actin with immunohistochemistry in the CA1, CA3, and dentate gyrus regions of the hippocampus and, finally, the number of dendritic spines and their dynamics using Golgi-Cox staining. We found that ionotropic glutamate receptor function blockade at neonatal age causes a reduction in short and long-term memory in adulthood and a reduction in the expression of synaptophysin and actin protein levels in the hippocampus regions studied. This blockade also reduced the number of dendritic spines and modified dendritic dynamics in the CA1 region. The antagonism of the three types of ionotropic glutamate receptors reduced the mushrooms and bifurcated types of spines and increased the thin spines. The number of stubby spines was reduced by D-AP5, increased by UPB-302, and not affected by GYKI-53655. Our results indicate that the blockade of neonatal ionotropic glutamate receptors produces alterations that persist until adulthood.
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In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied... more
In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied the effect of nOBX on the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors during development. The behavioral effects of nOBX (postnatal day 7, PD7) were investigated in pre- (PD30) and post-pubertal (PD60) Wistar rats. NMDA receptor activity was measured with [(125)I]MK-801 in the brain regions associated with the olfactory circuitry. A significant increase in the novelty-induced locomotion was seen in the pre-pubertal nOBX rats. Although the locomotor effect was less marked than in pre-pubertal rats, the nOBX rats tested post-pubertally failed to habituate to the novel situation as quickly as the sham- and normal- controls. Pre-pubertally, the head-dipping behavior was enhanced in nOBX rats compared with sham-operated and normal controls, while normal exploratory behavior was observed between groups in adulthood. In contrast, social interaction was increased in post-pubertal animals that underwent nOBX. Both pre- and post-pubertal nOBX rats recovered olfaction. Interestingly, pre-pubertal rats showed a significant increase in the [(125)I]MK-801 binding in the piriform cortex, dorsal hippocampus, inner and outer layers of the frontal cortex and outer layer of the cingulate cortex. At post-pubertal age, no significant differences in [(125)I]MK-801 binding were observed between groups at any of the brain regions analyzed. These results suggest that nOBX produces pre-pubertal behavioral disturbances and NMDA receptor changes that are transitory with recovery of olfaction early in adulthood.
Research Interests: Endocrinology, Neuroscience, Medicine, Pergamon, Hippocampus, and 15 morePregnancy, Internal Medicine, Female, Animals, Male, Interpersonal Relations, Piriform Cortex, Age Factors, Olfactory Bulb, Exploratory Behavior, Protein Binding, Olfactory Pathways, Neurosciences, Motor activity, and NMDA receptor
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Research Interests: Neuroscience, Cognitive Science, Chemistry, Drug interactions, Medicine, and 15 moreHippocampus, Classical Conditioning, Glutamate, Mice, Animals, Male, Facilitation, Associative learning, Cholinergic Receptor, Neurosciences, Glutamic Acid, Blinking, Agonist, Glutamate Receptor, and Electric stimulation
Research Interests: Psychology, Biology, Neuropharmacology, Medicine, Hippocampus, and 15 moreCell line, Glutamate, Animals, Activation, Rats, Desensitization, Kainate Receptors, Neurosciences, Glutamic Acid, Drug Tolerance, Agonist, Glutamate Receptor, Kainic acid, Rate Constant, and Pharmacology and pharmaceutical sciences
Objetivo. Describir el estado actual de conocimientos sobre la fisiologia de los receptores de glutamato de tipo kainato como moduladores de la transmision sinaptica inhibidora gabergica en el hipocampo. Desarrollo. En la sinapsis... more
Objetivo. Describir el estado actual de conocimientos sobre la fisiologia de los receptores de glutamato de tipo kainato como moduladores de la transmision sinaptica inhibidora gabergica en el hipocampo. Desarrollo. En la sinapsis interneurona-celula principal de la capa CA1 del hipocampo, se produce una depresion de la transmision sinaptica inhibidora gabergica por la activacion de receptores de kainato situados en el terminal presinaptico de las interneuronas. Esta disminucion de la liberacion de GABA involucra una accion metabotropica, de manera que requiere la activacion de una proteina G sensible a la toxina pertusica y la activacion de la proteina cinasa C. En estas mismas interneuronas, tambien existe una poblacion de receptores de kainato de accion ionotropica en el compartimento somatodendritico cuya activacion las despolariza y produce una liberacion masiva de neurotransmisor. Muy recientemente, se ha demostrado que la activacion de receptores de kainato por concentraciones submicromolares de agonista puede producir un aumento de la liberacion de GABA. Este efecto se ha descrito sobre todo en las sinapsis interneurona-interneurona, si bien el mecanismo de accion de los receptores de kainato para producir este efecto aun no se ha descrito. Conclusiones. Los receptores de kainato actuan en el hipocampo como moduladores de la liberacion de GABA, inhibiendola o incrementandola, de modo que contribuyen al mantenimiento del exquisito equilibrio de la excitabilidad neuronal. En condiciones anormales pueden producir un marcado desequilibrio de esta excitabilidad y dar lugar, entre otras alteraciones, a patrones de disparo de tipo epileptico.
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Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic... more
Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control li...
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Research Interests: Endocrinology, Cognitive Science, Cardiovascular disease, Antioxidants, Cardiac Hypertrophy, and 15 moreBlood Pressure, Animal Feed, Animals, Drinking Water, American, Dendrites, Fructose, Endothelial dysfunction, Clinical Sciences, Cardiovascular system, Biological markers, Heart Ventricles, Experimental Model, ENOS, and Endothelial nitric oxide synthase
Research Interests: Neuroscience, Fear, Long Term Potentiation, Biology, Medicine, and 15 moreLearning, Memory, Hippocampus, Classical Conditioning, Mice, Animals, Neuronal Plasticity, Amygdala, Phosphorylation, Maze Learning, binding sites, Flail chest, Protein tyrosine kinases, Medical and Health Sciences, and In Vitro Techniques
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Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with... more
Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3- and 10-month-old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10-month-old APPLd2 mice also presented deficits in paired-pulse facilitation and long-term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimer's disease, and that specific learning tasks could have a relevant diagnostic value.
Research Interests: Neuroscience, Psychology, Cognitive Science, Long Term Potentiation, Medicine, and 15 moreTransgenic Mice, Hippocampus, Classical Conditioning, Evoked Potentials, Humans, Mutation, Mice, Animals, Male, Reaction Time, Associative learning, European, Alzheimer Disease, Neurosciences, and Amyloid Beta Precursor Protein
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Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson's disease (PD). The dopaminergic agonists like... more
Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson's disease (PD). The dopaminergic agonists like apomorphine are related to oxidative processes that could induce cell damage and the functional impairment of some structures in the brain. However, most information about apomorphine in literature is focused on the improvement of the motor problems characteristic of PD, but little is known about the effects on cognitive behaviors and brain structures indirectly related to motor function. The presence of dopaminergic receptors in the hippocampus has recently been discovered, in connection with cognitive behaviors like learning and memory, these receptors are needed in neuronal plasticity. There has been a growing interest to know if this structure could be compromised by the effect of apomorphine and elucidate if part of the cognitive impairment prese...
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In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types... more
In the classical view, postsynaptic NMDA receptors (NMDARs) trigger Hebbian plasticity via Ca influx. However, unconventional presynaptic NMDARs (preNMDARs) which regulate both long-term and short-term plasticity at several synapse types have also been found. A lack of sufficiently specific experimental manipulations and a poor understanding of how preNMDARs signal have contributed to long-standing controversy surrounding these receptors. Although several prior studies linked preNMDARs to neocortical timing-dependent long-term depression (tLTD), a recent study argues that the NMDARs are actually postsynaptic and signal metabotropically, that is, without Ca. Other recent work indicates that, whereas ionotropic preNMDARs signaling controls evoked release, spontaneous release is regulated by metabotropic NMDAR signaling. We argue that elucidating unconventional NMDAR signaling modes-both presynaptically and metabotropically-is key to resolving the preNMDAR debate.
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Research Interests: Neurobiology Of Disease, Spatial Memory, Long Term Potentiation, Down Syndrome, Transgenic Mice, and 12 moreAnimals, Male, Synaptic Transmission, Clinical Sciences, Long Term Memory, Memory Disorders, Academic, Sirolimus, Maze Learning, Neurosciences, Brain-derived neurotrophic factor (BDNF), and Tissue culture techniques
We studied conditional self-discrimination (CSD) in rats and compared the neuronal cytoarchitecture of untrained animals and rats that were trained in self-discrimination. For this purpose, we used thirty 10-week-old male rats were... more
We studied conditional self-discrimination (CSD) in rats and compared the neuronal cytoarchitecture of untrained animals and rats that were trained in self-discrimination. For this purpose, we used thirty 10-week-old male rats were randomized into three groups: one control group and two conditioning groups: a comparison group (associative learning) and an experimental group (self-discrimination). At the end of the conditioning process, the experimental group managed to discriminate their own state of thirst. After the conditioning process, dendritic morphological changes in the pyramidal neurons of the prefrontal cortex and CA1 region of the dorsal hippocampus were evaluated using Golgi-Cox stain method and then analyzed by the Sholl method. Differences were found in total dendritic length and spine density. Animals trained in self-discrimination showed an increase in the dendritic length and the number of dendritic spines of neurons of the prefrontal cortex and CA1 region of the dorsal hippocampus. Our data suggest that conditional self-discrimination improves the connectivity of the prefrontal cortex and dorsal CA1, which has implications for memory and learning processes. Synapse 69:543-552, 2015. © 2015 Wiley Periodicals, Inc.
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Excitatory amino acids (glutamate and aspartate) form the mainstay of synaptic transmission in the central nervous system. By the same token, dysfunctional, excitotoxic activity of excitatory amino acids can lead to and/or become... more
Excitatory amino acids (glutamate and aspartate) form the mainstay of synaptic transmission in the central nervous system. By the same token, dysfunctional, excitotoxic activity of excitatory amino acids can lead to and/or become instrumental in the progression of a number of neurological and neurodegenerative conditions. Dementia due to Alzheimer's disease (AD) is characterized by extracellular plaques containing amyloid (Aβ peptide) which, together with its disruption of dendritic morphology, affects glutamate (AMPA and NMDA) receptor function to alter glutamatergic transmission. The progressive neurodegeneration of nigrostriatal neurons in Parkinson's disease (PD) may in part arise as a result of overactivity of glutamatergic inputs from the cortex and subthalamic nuclei, presenting the utility of respective antagonism and agonism of stimulatory and inhibitory metabotropic glutamate receptors (mGluR) in PD therapeutics. Huntington's disease (HD) manifests as atrophy o...
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Ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA)- and AMPA-type, as well as metabotropic glutamate receptors have been extensively invoked in plasticity. Until relatively recently, however, kainate-type receptors (KARs)... more
Ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA)- and AMPA-type, as well as metabotropic glutamate receptors have been extensively invoked in plasticity. Until relatively recently, however, kainate-type receptors (KARs) had been the most elusive to study because of the lack of appropriate pharmacological tools to specifically address their roles. With the development of selective glutamate receptor antagonists, and knockout mice with specific KAR subunits deleted, the functions of KARs in neuromodulation and synaptic transmission, together with their involvement in some types of plasticity, have been extensively probed in the central nervous system. In this review, we summarize the findings related to the roles of KARs in short- and long-term forms of plasticity, primarily in the hippocampus, where KAR function and synaptic plasticity have received avid attention.
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Neonatal basolateral amygdala (nBLA) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nBLA lesions result in significant decreases in the dendritic... more
Neonatal basolateral amygdala (nBLA) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nBLA lesions result in significant decreases in the dendritic spine number of layer 3 prefrontal cortex (PFC) pyramidal cells and medium spiny neurons of the nucleus accumbens (NAcc), which all changes after puberty. At present, we aimed to evaluate the effect of this lesion in pyramidal neurons of CA1 of the ventral hippocampus (VH) and layer 5 of the PFC. In order to assess the effects of nBLA lesions on the dendritic morphology of the PFC and VH neurons, we carried out nBLA lesions in rats on postnatal day (PD) 7, and then we studied the dendritic morphology of these two limbic subregions at prepubertal (PD35) and postpubertal (PD60) ages. Dendritic characteristics were measured by Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of nBLA lesions on the prepulse inhibition (PPI) and acoustic startle responses. The nBLA lesion induced a significant increase in dendritic length of layer 5 pyramidal neurons of the PFC at both ages, with a decrease in the dendritic spines density after puberty. The spine density of CA1 VH pyramidal neurons showed significant decreases at both ages. PPI was decreased in adulthood in the animals with an nBLA lesion. These results show that an nBLA lesion alters the dendritic morphology at the level of the PFC and VH in distinct ways before puberty, suggesting a disconnection between these limbic structures at an early age, and increasing our understanding of the implications of the VH in early amygdala dysfunction in schizophrenia.
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Research Interests: Learning, Hippocampus, Learning and Memory, Classical Conditioning, Humans, and 15 moreCerebral Cortex, Animals, Male, Electromyography, Associative learning, Clinical Sciences, Computer Program, Genetically Modified, Cognitive Function, Conditioning, Age Factors, Cognition disorders, Biochemistry and cell biology, Eyeblink Conditioning, and Electric stimulation
Several studies in rodents have shown that dysfunctions of the thalamic reticular nucleus (TRN) result in deficits of sensory gating and attentional processes, two core features of schizophrenia. TRN receives inputs from the prefrontal... more
Several studies in rodents have shown that dysfunctions of the thalamic reticular nucleus (TRN) result in deficits of sensory gating and attentional processes, two core features of schizophrenia. TRN receives inputs from the prefrontal cortex (PFC) and hippocampal formation, two structures which send excitatory projections to the nucleus accumbens (NAcc) and are interconnected with the basolateral amygdala (BLA). Here we determined whether (and which) changes occurred four weeks after a TRN lesion in the dendritic morphology of pyramidal neurons of layers 3 and 5 of the PFC, neurons of ventral and dorsal hippocampus, BLA, and the medium spiny neurons of the NAcc. Dendritic morphology and characteristics were measured by using Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of TRN lesion on exploratory behavior assessed by hole-board test and locomotor activity induced by a novel environment. We found that TRN damage induced a reduction in the exploratory behavior measured by hole-board test with neuronal hypotrophy in PFC (layer 5), CA1 ventral hippocampus and NAcc neurons. Taken together, these data suggest that the behavioral and morphological effects of TRN lesion are, at least partially, mediated by limbic subregions with possible consequences for schizophrenia-related behaviors.