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Javier DeFelipe

Publications and source records attributed to Javier DeFelipe.

At least 19 recordsLinked to original sources
PubMed2006

Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells.

The axon initial segment (AIS) of pyramidal cells is a critical region for the generation of action potentials and for the control of pyramidal cell activity. Here we show that Na+ and K+ voltage-gated channels, together with other molecules involved in the localization of ion channels, are distributed asymmetrically in the AIS of pyramidal cells situated in the human temporal neocortex. There is a high density of Na+ channels distributed along the length of the AIS together with the associated proteins spectrin betaIV and ankyrin G. In contrast, Kv1.2 channels are associated with the adhesion molecule Caspr2, and they are mostly localized to the distal region of the AIS. In general, the distal region of the AIS is targeted by the GABAergic axon terminals of chandelier cells, whereas the proximal region is innervated, mostly by other types of GABAergic interneurons. We suggest that this molecular segregation and the consequent regional specialization of the GABAergic input to the AIS of pyramidal cells may have important functional implications for the control of pyramidal cell activity.

Adult↗
PubMed2006

Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy.

The biology underlying epileptic brain activity in humans is not well understood and likely depends on changes in gene expression. We performed a microarray transcriptome profiling of 12 anterolateral temporal cortical samples originating from five individuals who suffered with temporal lobe epilepsy for at least 10 years. Prior to partial lobectomy, intraoperative electrocorticography was performed on the cortical surface of each patient. These recordings showed characteristic differences in frequency and amplitude that were defined as "spiking" (abnormal) or "non-spiking" (normal). Between the transcriptome of the two sample groups, transferrin (TF) was the most differentially expressed gene. Furthermore, gene expression profiling also revealed a downregulation of multiple GABA system-related genes (GABRA5, GABRB3, ABAT) in the spiking samples and an upregulation of oligodendrocyte and lipid metabolism transcripts (MOG, CA2, CNP, SCD, PLP1, FA2H, ABCA2). In addition, several transcripts related to the classical MAPK cascade showed expression level alterations between the spiking and non-spiking samples (G3BP2, MAPK1, PRKAR1A, and MAP4K4). Out of 12 genes chosen for verification by RT qPCR, 9 showed significant expression changes in the microarray-predicted direction. Furthermore, the microarray and qPCR data were highly correlated (r = 0.98; P < 0.001). We conclude that abnormal electrical brain activity in the spiking samples is strongly correlated with gene expression changes and we speculate that some of the observed transcriptome changes may be directly involved in the induction or prevention of the ictal events seen in epilepsy.

Action Potentials↗
PubMed2006

Double-bouquet cells in the monkey and human cerebral cortex with special reference to areas 17 and 18.

The detailed microanatomical study of the human cerebral cortex began in 1899 with the experiments of Santiago Ramón y Cajal, who applied the Golgi method to define the structure of the visual, motor, auditory and olfactory cortex. In the first article of this series, he described a special type of interneuron in the visual cortex capable of exerting its influence in the vertical dimension. These neurons are now more commonly referred to as double-bouquet cells (DBCs). The DBCs are readily distinguished owing to their characteristic axons that give rise to tightly interwoven bundles of long, vertically oriented axonal collaterals resembling a horsetail (DBC horsetail). Nevertheless, the most striking characteristic of these neurons is that they are so numerous and regularly distributed that the DBC horsetails form a microcolumnar structure. In addition, DBCs establish hundreds of inhibitory synapses within a very narrow column of cortical tissue. These features have generated considerable interest in DBCs over recent years, principally among those researchers interested in the analysis of cortical circuits. In the present chapter, we shall discuss the morphology, synaptic connections and neurochemical features of DBCs that have been defined through the study of these cells in different cortical areas and species. We will mainly consider the immunocytochemical studies of DBCs that have been carried out in the visual cortex (areas 17 and 18) of human and macaque monkey. We will see that there are important differences in the morphology, number and distribution of DBC horsetails between areas 17 and 18 in the primate. This suggests important differences in the microcolumnar organization between these areas, the functional significance of which awaits detailed correlative physiological and microanatomical studies.

Animals↗
PubMed2006

Brain plasticity and mental processes: Cajal again.

The year 2006 marks the 100th anniversary of the first Nobel Prize for Physiology or Medicine for studies in the field of the Neurosciences jointly awarded to Camillo Golgi and Santiago Ramón y Cajal for their key contributions to the study of the nervous system. This award represented the beginning of the modern era of neuroscience. Using the Golgi method, Cajal made fundamental, but often unappreciated, contributions to the study of the relationship between brain plasticity and mental processes. Here, I focus on some of these early experiments and how they continue to influence studies of brain plasticity.

Brain↗
PubMed2005

Specialization in pyramidal cell structure in the cingulate cortex of the Chacma baboon (Papio ursinus): an intracellular injection study of the posterior and anterior cingulate gyrus with comparative notes on the macaque and vervet monkeys.

This study forms part of an ongoing investigation of pyramidal cell structure in the cingulate cortex of primates. Recently we have demonstrated that layer III pyramidal cells in the anterior cingulate gyrus are considerably larger, more branched and more spinous than those in the posterior cingulate gyrus (areas 24 and 23, respectively) in the macaque and vervet monkeys. Moreover, the extent of the interareal difference in specialization in pyramidal cell structure differed between the two species. These data suggest that pyramidal cell circuitry may have evolved differently in these closely related species. Presently there are too few data to speculate on what is selecting for this specialization in structure. Here we extend the basis for comparison by studying pyramidal cell structure in cingulate gyrus of the Chacma baboon (Papio ursinus). Methodology used here is the same as that for our previous studies: intracellular injection of Lucifer Yellow in flat-mounted cortical slices. We found that pyramidal cells in anterior cingulate gyrus (area 24) were more branched and more spinous than those in posterior cingulate gyrus (area 23). Moreover, the complexity in pyramidal cell structure in both the anterior and posterior cingulate gyrus of the baboon differed to that in the corresponding regions in either the macaque or vervet monkeys.

Animals↗
PubMed2005

Dendritic size of pyramidal neurons differs among mouse cortical regions.

Neocortical circuits share anatomical and physiological similarities among different species and cortical areas. Because of this, a 'canonical' cortical microcircuit could form the functional unit of the neocortex and perform the same basic computation on different types of inputs. However, variations in pyramidal cell structure between different primate cortical areas exist, indicating that different cortical areas could be built out of different neuronal cell types. In the present study, we have investigated the dendritic architecture of 90 layer II/III pyramidal neurons located in different cortical regions along a rostrocaudal axis in the mouse neocortex, using, for the first time, a blind multidimensional analysis of over 150 morphological variables, rather than evaluating along single morphological parameters. These cortical regions included the secondary motor cortex (M2), the secondary somatosensory cortex (S2), and the lateral secondary visual cortex and association temporal cortex (V2L/TeA). Confirming earlier primate studies, we find that basal dendritic morphologies are characteristically different between different cortical regions. In addition, we demonstrate that these differences are not related to the physical location of the neuron and cannot be easily explained assuming rostrocaudal gradients within the cortex. Our data suggest that each cortical region is built with specific neuronal components.

Animals↗
PubMed2005

Pyramidal cell specialization in the occipitotemporal cortex of the Chacma baboon (Papio ursinus).

Pyramidal cell structure varies systematically in occipitotemporal visual areas in monkeys. The dendritic trees of pyramidal cells, on average, become larger, more branched and more spinous with progression from the primary visual area (V1) to the second visual area (V2), the fourth (V4, or dorsolateral DL visual area) and inferotemporal (IT) cortex. Presently available data reveal that the extent of this increase in complexity parallels the expansion of occipitotemporal cortex. Here we extend the basis for comparison by studying pyramidal cell structure in occipitotemporal cortical areas in the chacma baboon. We found a systematic increase in the size of and branching complexity in the basal dendritic trees, as well as a progressive increase in the spine density along the basal dendrites of layer III pyramidal cells through V1, V2 and V4. These data suggest that the trend for more complex pyramidal cells with anterior progression through occipitotemporal visual areas is not a feature restricted to monkeys and prosimians, but is a widespread feature of occipitotemporal cortex in primates.

Animals↗
PubMed2005

Pyramidal cell specialization in the occipitotemporal cortex of the vervet monkey.

Pyramidal cells were injected intracellularly in fixed, flat-mounted cortical slices taken from the first and fourth visual areas (V1 and V4, respectively) and cytoarchitectonic areas TEO and TE of two age and gender-matched vervet monkeys and the size, branching complexity and spine density of their basal dendritic trees determined. In both animals, we found marked differences in the pyramidal cell phenotype between cortical areas. More specifically, a consistent trend for larger, more branched and more spinous pyramidal cells with progression through V1, V4, TEO and TE was observed. These findings support earlier reports of interareal specialization in pyramidal cell structure in occipitotemporal visual areas in the macaque monkey.

Animals↗
PubMed2005

Double bouquet cell in the human cerebral cortex and a comparison with other mammals.

Double bouquet cells (DBCs) are neocortical gamma-aminobutyric acid (GABA)ergic interneurons characterized by the vertical bundling of its axon, which are generally termed "bundles" or "horse-tails." Using immunocytochemistry for the calcium binding protein calbindin, we have analyzed the morphology, density, and distribution of DBC horse-tails in different cortical areas of the human cortex (Brodmann's areas 10, 4, 3b, 22, 18, and 17). Although DBC horse-tails were very numerous and regularly distributed in all cortical areas, variations were observed both in terms of morphology and density. We distinguished two major classes of DBC horse-tails: the thicker complex type (type I) that had more axon collaterals; and the simple type (type II). The density of DBC horse-tails was significantly higher in areas 17, 18, 22, and 4 than in areas 3b and 10. Moreover, the proportion of type I and type II DBC horse-tails varied in the cortical areas studied. We also examined the distribution of DBC horse-tails in frontal, parietal, and occipital areas of different mammalian species. We found DBCs to be present in carnivores but not in rodents, lagomorphs, or artiodactyls. In carnivores, relatively few DBC horse-tails can be identified and they were generally found in the occipital cortex. Therefore, there is significant variability in the morphology and distribution of DBC horse-tails in different species and cortical areas. We conclude that, although these interneurons may be an important element in the organization of cortical microcolumns in primates, this is not the case in other mammalian species.

Acinonyx↗
PubMed2005

Catecholaminergic innervation of pyramidal neurons in the human temporal cortex.

In the human neocortex, catecholaminergic connections modulate the excitatory inputs of pyramidal neurons and are involved in higher cognitive functions. Catecholaminergic fibers form a dense network in which it is difficult to distinguish whether or not target specificity exists. In order to shed some light on this issue, we set out to quantify the catecholaminergic innervation of pyramidal cells in different layers of the human temporal cortex (II, IIIa, IIIb, V and VI). For this purpose, pyramidal cells were labeled in human cortical tissue by injecting them with Lucifer Yellow, and then performed immunocytochemistry for the rate limiting catecholamine synthesizing enzyme tyrosine hydroxylase (TH) to visualize catecholaminergic fibers in the same sections. Injected cells were reconstructed in three dimensions and appositions were quantified (n = 1503) in serial confocal microscopy images of each injected cell (n = 71). We found TH-immunoreactive appositions (TH-ir) in all the pyramidal cells analyzed, in both the apical and basal dendritic regions. In general, the density of TH-ir apposition was greater in layers II, V and VI than in layers IIIa and IIIb. Furthermore, TH-ir appositions showed a regular distribution in almost all dendritic compartments of the apical and basal dendritic arbors across all layers. Hence, it appears that all pyramidal neurons in the human neocortex receive catecholaminergic afferents in a rather regular pattern, independent of the layer in which they are located. Since pyramidal cells located in different layers are involved in different intrinsic and extrinsic circuits, these results suggest that catecholaminergic afferents may modify the function of a larger variety of circuits than previously thought. Thus, this aspect of human cortical organization is likely to have important implications in cortical function.

Adult↗
PubMed2003

Different populations of tyrosine-hydroxylase-immunoreactive neurons defined by differential expression of nitric oxide synthase in the human temporal cortex.

In the mammalian neocortex, neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, constitute an enigmatic and ill-defined group of aspiny non-pyramidal cells. In the human neocortex, these neurons are mostly found in layers V-VI, the same layers in which another conspicuous group of nitrergic non-pyramidal cells are found - those containing nitric oxide synthase (nNOS) and that can be labeled by nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry. The main aim of the present study was to determine the extent to which neurons and fibers containing TH, NADPHd or nNOS co-localize in the human temporal cortex, using immunocytochemistry and NADPHd histochemistry. Furthermore, we have quantified the degree to which axons immunoreactive (ir) for TH contact the somata of neurons by co-labeling with the neuron-specific nuclear protein NeuN. As a result, we show that the population of TH-ir neurons can be subdivided into two main neurochemical groups: those expressing nNOS (26%) and those that do not (74%). There was no co-localization of TH with nNOS in the prominent horizontally oriented plexus of fibers in layer I and we did not observe any double bouquet cells, chandelier cells or basket cells that contained TH. Finally, we observed that only 6% of the TH-ir axonal boutons examined (n = 1724) could be seen to contact neuronal somata. Thus, most TH-ir axons must form synapses with dendrites. In conjunction with data from previous studies, these results suggest that TH is found in different neurochemically defined subpopulations of non-pyramidal neurons in layers V-VI of the human temporal cortex. Consequently, it appears that a partial overlap of the catecholaminergic and nitrergic systems is probably due to the intrinsic cortical TH-nNOS-ir neurons.

Adult↗
PubMed2002

GABABR1 receptor protein expression in human mesial temporal cortex: changes in temporal lobe epilepsy.

Immunocytochemistry was used to examine gamma-aminobutyric acid beta (GABA)(B)R1a-b protein expression in the human hippocampal formation (including dentate gyrus, hippocampus proper, subicular complex, and entorhinal cortex) and perirhinal cortex. Overall, GABA(B)R1a-b immunostaining was intense and widespread but showed differential areal and laminar distributions of labeled cells. GABA(B)R1a-b-immunoreactive (-ir) neurons were found in the three main layers of the dentate gyrus, the most intense labeling being present in the polymorphic layer, whereas the granule cells were moderately immunoreactive. Except for slight variations, similar distribution patterns of GABA(B)R1a-b immunostaining were found along the different subfields of the Ammon's horn (CA1-CA4). The highest density of GABA(B)R1a-b-ir neurons was localized in the stratum pyramidale, where virtually every pyramidal cell was intensely immunoreactive, including the proximal part of the apical dendrites. Within the subicular complex, a more intense GABA(B)R1a-b immunostaining was found in the subiculum than in the presubiculum or parasubiculum, especially in the pyramidal and polymorphic cell layers. In the entorhinal cortex, distribution of GABA(B)R1a-b immunoreactivity was localized mainly in both pyramidal and nonpyramidal cells of layers II, III, and VI and in the superficial part of layer V, with layers I, IV, and deep layer V being less intensely stained. In the perirhinal cortex, the most intense GABA(B)R1a-b immunoreactivity was located in the deep part of layer III and in layer V and was mainly confined to medium-sized and large pyramidal cells. Thus, the differential expression, but widespread distribution, of GABA(B)R1a-b protein found in the present study suggests the involvement of GABA(B) receptors in many circuits of the human hippocampal formation and adjacent cortical structures. Interestingly, the hippocampal formation of epileptic patients (n = 8) with hippocampal sclerosis showed similar intensity of GABA(B)R1a-b immunostaining in the surviving neurons located within or adjacent to those regions presenting neuronal loss than in the controls. However, surviving neurons in the granule cell layer of the dentate gyrus displayed a significant reduction in immunostaining in 7 of 8 patients. Therefore, alterations in inhibitory synaptic transmission through GABA(B) receptors appears to affect differentially certain hippocampal circuits in a population of epileptic patients. This reduction in GABA(B)R1a-b expression could contribute to the pathophysiology of temporal lobe epilepsy.

Adult↗
PubMed2002

Cortical interneurons: from Cajal to 2001.

After the collective work of many investigators, beginning with the early studies of Cajal, the following main [figure: see text] conclusions may be drawn regarding the morphology, biochemical characteristics and synaptic connections of interneurons: 1. Interneurons show a great variety of morphological, biochemical and physiological types. They constitute approximately 15-30% of the total population of neurons. 2. Because of the heterogeneity of interneurons and the lack of consensus as to which characteristics are essential for an individual neuron to be considered a member of a given cell type, there is no definitive classification of interneurons. Nevertheless, certain interneurons can be readily recognized by their unique morphological characteristics, or they can be more generally divided into subgroups on the basis of their biochemical characteristics, patterns of axonal arborization, or synaptic connections with pyramidal cells. 3. All interneurons have a more or less dense axonal arborization distributed near the cell body, mainly within the area occupied by their dendritic field. However, some interneurons may display, in addition, prominent long, horizontal or vertical axonal collaterals. [figure: see text] 4. Most interneurons form symmetrical synapses with both pyramidal cells and other interneurons, with the exception of chandelier cells, which only form synapses with the axon initial segment of pyramidal cells. Furthermore, interneurons are not only connected by chemical synapses (unidirectional connections), but they may also form electrical synapses through gap junctions (bidirectional) in a specific manner. 5. With the exception of chandelier cells, other types of interneurons include among their synaptic targets more than one type of postsynaptic element. But the degree of preference for these postsynaptic elements varies markedly between different types of interneurons. 6. The number of synapses made by a single axon originating from a given interneuron on another neuron is on the order of ten or less. Since, in general, cortical neurons receive many more interneuronal (symmetrical) synapses (on the order of a few hundred or thousand), a considerable convergence of various types of interneurons to pyramidal cells and interneurons appears to occur. 7. Most interneurons are GABAergic and also express a number of different neurotransmitters (or their synthesizing enzymes), neuropeptides and calcium-binding proteins. Thus, interneurons are, biochemically, widely heterogeneous. 8. Some of the morphologically identifiable neurons can be characterized by their particular biochemical characteristics, and some biochemically definable subgroups of interneurons display a particular morphology. However, different morphological types of GABAergic neurons may share one or several neurotransmitters, neuroactive substances and/or other molecular markers. Therefore, a great variety of subgroups of morphologically and biochemically identifiable neurons exist. 9. Some interneurons appear to be common to all species and, therefore, may be considered as basic elements of cortical circuits, whereas others may represent evolutionary specializations which are characteristic of particular mammalian subgroups and, thus, cannot be taken as essential, or general, features of cortical organization. 10. Given the complexity of cortical circuits and the areal and species differences, it is impossible to draw a "sufficiently" complete basic diagram of cortical microcircuitry that is valid for all cortical areas and species.

Animals↗
PubMed2002

Sesquicentenary of the birthday of Santiago Ramón y Cajal, the father of modern neuroscience.

The appearance of Santiago Ramón y Cajal in the world of neuroscience provoked a radical change in the course of its history. Cajal's studies of the microanatomy of virtually the whole CNS and his observations regarding degeneration and regeneration, together with his theories about the function, development and plasticity of the nervous system, had a profound impact on researchers of his era. These studies represent the roots of what are today some of the most exciting areas of discovery in terms of the structure and function of the brain in both sickness and health.

Central Nervous System↗
PubMed2002

PSA-NCAM immunoreactivity in chandelier cell axon terminals of the human temporal cortex.

In the adult central nervous system, the expression of polysialylated forms of the cell-surface glycoprotein NCAM (PSA-NCAM) is thought to be confined to areas particularly susceptible to plastic changes. In the present study, PSA-NCAM was found to be expressed in the somata, dendrites and axonal processes of some neurons, including cartridge-like elements, which according to our criteria, were identified as chandelier cell axon terminals (chandelier terminals), in the adult human entorhinal cortex and neocortex. These chandelier terminals were very numerous in layers II and III, whereas in deeper layers they were found only occasionally. Double immunocytochemical staining for PSA-NCAM with parvalbumin (PV), with GABA transporter (GAT-1) or with the 5-HT(1A) serotonin receptor allowed us to verify them as true chandelier terminals. Nearly all (92-95%) PV-immunoreactive (-ir) and GAT-1-ir chandelier terminals in layers II and III coexpressed PSA-NCAM. Most of the PSA-NCAM-ir chandelier terminals (89-98%) were also labeled for PV and GAT-1. The results suggest that chandelier terminals in layers II and III of the human entorhinal cortex and temporal neocortex might be particularly susceptible to plastic changes.

Adult↗
PubMedDate not supplied

Microstructure of the neocortex: comparative aspects.

The appearance of the neocortex, its expansion, and its differentiation in mammals, represents one of the principal episodes in the evolution of the vertebrate brain. One of the fundamental questions in neuroscience is what is special about the neocortex of humans and how does it differ from that of other species? It is clear that distinct cortical areas show important differences within both the same and different species, and this has led to some researchers emphasizing the similarities whereas others focus on the differences. In general, despite of the large number of different elements that contribute to neocortical circuits, it is thought that neocortical neurons are organized into multiple, small repeating microcircuits, based around pyramidal cells and their input-output connections. These inputs originate from extrinsic afferent systems, excitatory glutamatergic spiny cells (which include other pyramidal cells and spiny stellate cells), and inhibitory GABAergic interneurons. The problem is that the neuronal elements that make up the basic microcircuit are differentiated into subtypes, some of which are lacking or highly modified in different cortical areas or species. Furthermore, the number of neurons contained in a discrete vertical cylinder of cortical tissue varies across species. Additionally, it has been shown that the neuropil in different cortical areas of the human, rat and mouse has a characteristic layer specific synaptology. These variations most likely reflect functional differences in the specific cortical circuits. The laminar specific similarities between cortical areas and between species, with respect to the percentage, length and density of excitatory and inhibitory synapses, and to the number of synapses per neuron, might be considered as the basic cortical building bricks. In turn, the differences probably indicate the evolutionary adaptation of excitatory and inhibitory circuits to particular functions.

Animals↗