Biomedical subjects
Publications and source records attributed to J C López-García.
CLINICAL CASE: This was a 15-month-old boy who had macular retinochoroidal lesions in both eyes following maternal varicella during pregnancy. DISCUSSION: The scars were suggestive of congenital chorioretinal infection, but because of negative serology and the clinical picture, we believe the problems are atypical macular colobomata.
A decade ago, our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology was essentially null. A plethora of recent studies has altered this situation profoundly such that kainate receptors are now regarded as key players in the modulation of transmitter release, as important mediators of the postsynaptic actions of glutamate, and as possible targets for the development of antiepileptic and analgesic drugs. In this review, we summarize our current knowledge of the properties of kainate receptors focusing on four key issues: 1) their structural and biophysical features, 2) the important progress in their pharmacological characterization, 3) their pre- and postsynaptic mechanisms of action, and 4) their involvement in a series of physiological and pathological processes. Finally, although significant progress has been made toward the elucidation of their importance for brain function, kainate receptors remain largely an enigma and, therefore, we propose some new roads that should be explored to obtain a deeper understanding of this young, but intriguing, class of proteins.
Glia calcium signaling has recently been identified as a potent modulator of synaptic transmission. We show here that the spatial expansion of calcium waves is mediated by ATP and subsequent activation of purinergic receptors. Ectopic expression of gap junction proteins, connexins (Cxs), leads to an increase in both ATP release and the radius of calcium wave propagation. Cx expression was also associated with a phenotypic transformation, and cortical neurons extended longer neurites when co-cultured with Cx-expressing than with Cx-deficient cells. Purinergic receptor activation mediated both these effects, because treatment with receptor antagonists restored the glia phenotype and slowed neurite outgrowth. These results identify a key role of ATP in both short-term calcium signaling events and in long-term differentiation regulated by glia.
Consistent with the epileptogenic and deleterious effects of the potent neurotoxin kainate, the activation of kainate receptors reduces the synaptic inhibition induced by the amino acid gamma-aminobutyric acid (GABA). Extrapolating from these data led to the conclusion that kainate receptors are located presynaptically. However, kainate directly depolarizes the inhibitory interneurons, causing them to fire repeatedly. This effect might indirectly decrease the size of inhibitory postsynaptic currents recorded from pyramidal cells and places in doubt the presynaptic location for kainate receptors. Here we show that both effects, membrane depolarization and the reduction of inhibitory potentials, can be dissociated by several means, particularly by the natural agonist of kainate receptors, glutamate. Indeed, when applied at low concentrations, glutamate inhibited GABA release without affecting the firing rate of GABA interneurons. These results indicate that CA1 interneurons contain two populations of kainate receptors, each with different agonist sensitivity and coupled to distinct signaling pathways.
We report a revised and improved isolation procedure for CA3-dendritic spines, most of them still in association with mossy fiber terminals resulting in a 7.5-fold enrichment over nuclei and a 29-fold enrichment over myelin. Additionally, red blood cells, medullated fibers, mitochondria and small synaptosomes were significantly depleted. We show by high resolution electron microscopy that this subcellular fraction contains numerous dendritic spines with a rich ultrastructure, e.g. an intact spine apparatus, membranous organelles, free and membrane-bound polyribosomes, endocytic structures and mitochondria. This improved experimental system will allow us to study aspects of post-synaptic functions at the biochemical and molecular level.
Long-term potentiation (LTP) is a long-lasting form of synaptic plasticity induced by brief repetitive afferent stimulation that is thought to be associated with learning and memory. It is most commonly studied in the hippocampus where it may last for several weeks, and involves the synthesis of new proteins that might play a structural role. In this review we summarize the evidence in favor of modifications of neuronal architecture during LTP. We focus our attention on changes occurring at the level of single synapses, including components of postsynaptic dendrites (dendritic spines, the postsynaptic density, and synaptic curvature), of presynaptic terminals, and the formation of new synapses. We conclude that although many morphological changes at various sites have been observed during LTP, there is no definitive proof in favor of structural changes associated with LTP. However, morphological modifications remain a valid candidate for mechanisms of learning and memory.
Several forms of long-term potentiation (LTP), a putative cellular mechanism for memory storage, have been described in the hippocampus. In this review, I discuss the mechanisms of induction and expression of LTP at the Schaffer collateral synapses and at the mossy fiber pathway. The early biochemical steps responsible for LTP at these two pathways are well understood. However, future studies should transcend the study of signal transduction systems and focus on the identification of the synaptic proteins that experience activity-dependent modifications, ultimate effectors of the plastic changes.
Synapses of the hippocampal mossy fiber pathway exhibit several characteristic features, including a unique form of long-term potentiation that does not require activation of the N-methyl-D-aspartate receptor by glutamate, a complex postsynaptic architecture, and sprouting in response to seizures. However, these connections have proven difficult to study in hippocampal slices because of their relative paucity (<0.4%) compared to commissural-collateral synapses. To overcome this problem, we have developed a novel dissociated cell culture system in which we have enriched mossy fiber synapses by increasing the ratio of granule-to-pyramidal cells. As in vivo, mossy fiber connections are composed of large dynorphin A-positive varicosities contacting complex spines (but without a restricted localization). The elementary synaptic connections are glutamatergic, inhibited by dynorphin A, and exhibit N-methyl-D-aspartate-independent long-term potentiation. Thus, the simplicity and experimental accessibility of this enriched in vitro mossy fiber pathway provides a new perspective for studying nonassociative plasticity in the mammalian central nervous system.
The complex circuitry of the CA3 region and the abundance of collateral connections has made it difficult to study the mossy fiber pathway in hippocampal slices and therefore to establish the site of expression of long-term potentiation at these synapses. Using a novel cell culture system, we have produced long-term potentiation of the elementary synaptic connections on single CA3 pyramidal neurons following tetanic stimulation of individual dentate gyrus granule cells. As is the case for the hippocampal slice, this potentiation was independent of N-methyl-D-aspartate receptor activation, was simulated by application of forskolin, and its induction did not require any modulatory input. The increase in synaptic strength was accompanied by a reduction in the number of failures of transmission and by an increase in the coefficient of variation of the responses and was prevented by presynaptic injection of an inhibitor of protein kinase A. These findings show that mossy fiber long-term potentiation has a presynaptic locus and that its expression is dependent on protein kinase A.
There is evidence that the cholinergic system modulates, in a circadian and asymmetric way, the neural activity involved in the regulation of ovulation. In the present study we measured choline acetyltransferase (ChAT) activity during the oestrous cycle in both sides of the preoptic-anterior hypothalamic area (POA-AHA) of the rat. The right side of POA-AHA showed significant changes in ChAT activity during the oestrous cycle. The activity of the enzyme was higher in the right side on the day of oestrous (47.3 +/- 3.2 nmol mg-1 protein 1 h-1 vs 25.8 +/- 2.4, p < 0.05), whilst on the second day of dioestrous the activity was higher in the left one (30.6 +/- 3.4 vs 20.0 +/- 1.5). The differences in the activity of ChAT observed support the idea of the existence of asymmetry in the POA-AHA cholinergic system which varies during the oestrous cycle.
The role of the nucleus basalis magnocellularis (NBM) in a variety of learning tasks is well known. Lesions of this nucleus result in a reduction of cholinergic transmission throughout a vast portion of the cortex. Because cholinergic transmission in the insular cortex seems to be important for the acquisition of conditioned taste aversion, the aim of the present work was to study the effects of bilateral chemically induced lesions of the NBM on this conditioning, as correlated with some cholinergic markers in the insular cortex. The effect on inhibitory avoidance was also studied. Lesions prevented the acquisition of the aversion and disrupted retention of the task in previously trained animals. Learning in the inhibitory avoidance paradigm was also notably affected. Postlesion reductions of choline acetyltransferase and acetylcholinesterase activities and of K(+)-stimulated [3H]acetylcholine release were found in the insular cortex. Further, in intact rats labeling of NBM neurons was observed by retrograde tracing after injection of Fluoro-Gold into the insular cortex. These findings indicate that the NBM is involved in the neural integration of feeding behavior and that its cholinergic projection to the insular cortex is one of the implicated neurotransmitter systems.
The gustatory neocortex (GN), final relay along the gustatory pathway, is a region of the brain involved in the neural integration of feeding behavior. Since information on the neurotransmitters in this nucleus is scarce, the aim of the present work was to establish whether acetylcholine (ACh), gamma-aminobutyric acid (GABA), dopamine and glutamate may act as transmitters within this structure. It was found that GN slices are able to release labeled GABA, ACh and glutamate but not dopamine. Additionally, it was possible to detect significant glutamic acid decarboxylase, choline acetyltransferase and acetylcholinesterase activities in GN homogenates. The activity of the two enzymes involved in acetylcholine metabolism was higher than that observed in other cortical regions. These findings suggest that GABA, ACh and glutamate probably are neurotransmitters in the GN, whereas dopamine is not.
Rats with lesions of the gustatory neocortex (GN) show deficits in the acquisition of taste aversion. Fetal GN grafts to a lesioned animal restore taste aversion learning and establish connections with the host brain. In this work, we examined whether the grafts are biochemically functional and whether this fact can be related to behavioral recovery. Gustatory or occipital cortices from rat fetuses were transplanted to GN-lesioned rats. Two months later, taste aversion recovery was tested and the release of labeled gamma-aminobutyric acid (GABA), acetylcholine (ACh), dopamine and glutamate from the grafted tissue was assayed. Fetal GN grafts promoted recovery of learning and released GABA, ACh and glutamate in response to K+ depolarization. Occipital cortex grafts did not induce behavioral recovery, although they were capable of releasing GABA. In contrast, these grafts did not release ACh. Moreover, GN-grafted rats in which behavioral recovery was not seen also failed to release ACh. These results are in agreement with previous findings that cholinergic transmission is important in the GN and suggest that ACh may play a role in the graft-mediated behavioral recovery observed in this model.
Rats showing disrupted taste aversion due to insular cortex (IC)-lesions received either IC-grafts with NGF, grafts without NGF, or NGF alone. An additional group served as lesioned controls. Only those animals that received IC-grafts with NGF recovered the ability to learn the conditioned taste aversion task, at 15 days post-graft. Choline acetyltransferase (ChAT) activity in the IC-grafts with, but not without NGF, was similar to the IC activity of unoperated controls. In contrast, glutamate decarboxylase activity was similar in all the groups. These findings suggest that IC-grafts associated with NGF induce recovery of learning abilities in IC-lesioned rats, which correlates with reestablishment of ChAT activity in the grafts at 15 days post-implantation.
OBJECTIVES: Comparative study of clinical characteristics and complications during induction, maintenance, and recovery in pediatric inhalational anesthesia between two commonly used fluoride agents (halothane and isoflurane). MATERIAL AND METHODS: We studied 66 children aged 1 month to 13 years undergoing general anesthesia for short lasting surgery who were divided into two groups of 33 patients each one: Isoflurane group and halothane group. Induction and maintenance anesthesia was performed with the corresponding inhalant agent. Parameters measured were duration of unconsciousness, time elapsed for intubation and recovery, heart rate, arterial blood pressure, and incidence of complications. RESULTS: Children anesthetized with isoflurane showed a shorter period of unconsciousness (1.55 +/- 0.11 min) than those anesthetized with halothane (1.91 +/- 0.12 min); whereas that the time required for intubation was significantly more prolonged (8.94 +/- 0.51 and 6.57 +/- 0.32 min, respectively). The incidence of complications was higher in the isoflurane group, mainly expressed as laryngeal spasm during the induction period. Both groups of patients showed a similar hemodynamic behaviour, although diastolic arterial pressure during maintenance anesthesia was significantly lower with isoflurane. Anesthesia recovery was faster and more predictable with isoflurane than with halothane. CONCLUSIONS: Anesthetic agent isoflurane is less appropriate than halothane for induction in pediatric anesthesia due to a high incidence of complications, specially laryngeal spasm.