Biomedical subjects

C Sotelo

Publications and source records attributed to C Sotelo.

At least 73 records · Page 4Linked to original sources

PubMed1992

Development of the olivocerebellar projection in the rat: I. Transient biochemical compartmentation of the inferior olive.

In the present study the early phases of the development of the inferior olive were examined by using immunocytochemical techniques. We observed that, from embryonic day 16 onward, antibodies against the calcium binding proteins parvalbumin and calbindin and the calcitonin gene related peptide stain partially overlapping territories of the inferior olive. This staining delimits a biochemical zonation of the inferior olive which is combinatory and transient. We have previously observed a biochemical parcellation of the cerebellar Purkinje cells which, like that of the inferior olive, is first observed at E16, involves the combined expression of marker proteins and is also transient. In order to know whether the biochemical compartmentations of the cerebellum and inferior olive arise independently, the time course of the development of the olivocerebellar projection was studied by anterograde and retrograde in vitro axonal tracing by using the fluorescent carbocyanine dye DiI. The olivocerebellar axons were found to reach the limit of the cerebellar plate at E16 and to enter it at E17. Even at this age the great majority of the climbing fibers are tightly fasciculated, which minimizes their interactions with the PC clusters. These observations indicate that the topographical heterogeneity of Purkinje cells and inferior olive neurons arise independently. The transient biochemical individualization of subgroups of neurons during development could contribute to recognition mechanisms.

Animals↗

PubMed1992

Development of the olivocerebellar projection in the rat: II. Matching of the developmental compartmentations of the cerebellum and inferior olive through the projection map.

A transient biochemical parcellation has been observed by immunocytochemical methods, during the perinatal development of both the inferior olive and the cerebellum. In the present study, we sought a relationship between this developmental compartmentation and the organization of the olivocerebellar projection. In the inferior olive, a transient parvalbumin immunoreactivity restricted to the dorsal cap of the medial accessory olive is observed around birth. The climbing fiber projection of the dorsal cap was identified in the cerebellum of newborn rats based on its parvalbumin immunoreactivity. The pattern of this projection, restricted to lobules IX and X of the vermis, and to the flocculus, is indistinguishable from that of the adult medial accessory olive, which was previously described from axonal tracing experiments. The parvalbumin immunoreactive climbing fibers were followed between birth and postnatal day 7. In the caudal vermis, Purkinje cell subpopulations can be identified between embryonic day 20 and postnatal day three, on the basis of their differential immunostaining with an antibody directed against a specific peptide, PEP 19. In lobule X, the parvalbumin immunoreactive climbing fibers form two sagittal bands on each side of the midline, one medial and one lateral. The medial parvalbumin immunoreactive climbing fiber band is coextensive with a PEP 19 negative Purkinje cell cluster, indicating a clear relationship between the biochemical parcellations of the cerebellum and inferior olive.

Animals↗

PubMed1992

Early development of the Lurcher cerebellum: Purkinje cell alterations and impairment of synaptogenesis.

The postnatal development of the heterozygous Lurcher (Lc/+) mouse cerebellum is characterized by Purkinje cell death with a concomitant reduction in granule cell number. In order to evaluate possible relationships between these two events, this study investigates early morphological abnormalities of the Purkinje cells and possible defects in the formation of their synaptic investment. Cerebella of Lurcher and control age-matched (from P8 to P16) mice were analysed by calbindin immunostaining, silver impregnation and quantitative electron microscopy. Direct signs of Purkinje cell anomaly are obvious from P8, four days before the onset of the necrotic process. These signs include the presence of axonal swellings and perinuclear clumps of chromatin, and a general delayed process of maturation, evidenced in cell bodies (incomplete development of the basal polysomal mass) and in dendritic trees (hyperspinous dendrites, delayed formation of proximal and distal compartments). Also from P8, the external granular layer is reduced in thickness. Despite these abnormalities, the onset of the synaptogenesis between Purkinje cells and their specific inputs (parallel fibres, climbing fibres and basket cell axons) takes place on schedule and, at P8, no defect has been noticed. On and after P10, the rate of parallel fibre synaptogenesis is decreased. Very few climbing fibres translocate from their perisomatic to their peridendritic locations, and basket cell axons fail to develop 'pinceau' formations. All these results suggest that before the death of the Purkinje cell by P12, there is an impaired maturation of these neurons provoked by the Lurcher gene action. The hypoplasia of the external granular layer and the altered synaptic investment of the Purkinje cell after P10 are considered to be consequences of the early Purkinje cell defect.

Animals↗

PubMed1992

New insight on the factors orienting the axonal outgrowth of grafted Purkinje cells in the pcd cerebellum.

Despite Purkinje cell replacement, leading to the repair of the cortical circuit of the pcd mouse cerebellum grafted with E12 cerebellar primordium, the reestablishment of the corticonuclear projection only occurs for some Purkinje cells and in a small percentage of grafted mice. In order to assess the importance of: (1) competition between host and grafted deep nuclei, and (2) the distance between the implants and the host deep nuclei, new grafted experiments have been performed. In the latter, solid grafts were taken from E13 or E14 donor embryos after removal of the region containing the postmitotic deep nuclear neurons, and randomly positioned at various cerebellar depths. With cortical implants, the absence of donor nuclear neurons is not sufficient to allow the axons of the grafted Purkinje cells that have invaded the host molecular layer to escape the confinement of this layer. The molecular/granular layer interface appears as an almost impassable obstacle, and the granule cell layer as a nonpermissive milieu. With grafts located between the host deep nuclei and the 4th ventricle (deep grafts), the grafted Purkinje cells project massively to the host nuclei, but they are unable to leave the implant and, therefore, they are not integrated in the deficient cortical circuit. Finally, when the grafts positioned in the central white matter (intermediate grafts) disrupt the integrity of the host granule cell layer, some of the grafted Purkinje cells invade the host molecular layer, while most of them remain within the implant. Some axons of the cortically integrated Purkinje cells, using the nearby graft as a bridge, seem able to innervate the host deep nuclei. The latter, in addition, receive a massive projection from the nonintegrated Purkinje cells. These results emphasize the ability of grafted Purkinje cells to specifically innervate their target host neurons, when either there is proximity, or when a permissive microenvironment for their axonal outgrowth is created by embryonic grafted cortical cerebellar neurons, filling the gap between the molecular layer and the deep nuclei of the host.

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PubMed1991

Early dendritic development of Purkinje cells in the rat cerebellum. A light and electron microscopic study using axonal tracing in 'in vitro' slices.

The early stages in the formation of Purkinje cell dendritic arbors have been analyzed using the horseradish peroxidase (HRP) 'in vitro' axonal tracing method, from embryonic day 19 (E19) to postnatal day 6 (P6). These stages comprise the transition from the bipolar Purkinje cell, at the end of its migration, to the phase of stellate cell with disoriented dendrites. Postmigratory Purkinje cells in the cortical plate exhibit poorly elaborated bipolar shapes, here named 'simple-fusiform' cells. They constitute the vast majority of labeled cells up to P0, and thereafter they decrease in number until P4. As a result of continuous outgrowth of new primary dendrites emerging from the apical pole but also from the basal and lateral aspects of the cell bodies, the Purkinje cells enter the 'complex-fusiform' phase, which peaks by P1 and slowly disappears by P6. The disappearance of 'complex-fusiform' cells is the result of an intense regressive process with resorption or retraction of the long dendrites that reaches a maximum by P3. We have called this stage: the Purkinje cell with 'regressive-atrophic' dendrites. This regression marks the initiation of the phase of the stellate cell, characterized by the explosive outgrowth of shorter perisomatic protrusions emerging in all directions. By P6, almost all the labeled Purkinje cells have attained this phase. The ultrastructural study of the labeled Purkinje cells has revealed that the transient dendrites of the fusiform cells have all the cytologic features of mature dendrites, particularly cytoskeletal elements (microtubules) and free polyribosomes. More importantly, axon terminals of unknown origin establish a few, constantly present, mature-like synaptic contacts on the dendritic shafts and spinous protrusions from P0, the earliest studied age. Their frequency increases on the Purkinje cells which enter the phase of stellate cell. Our results emphasize that the transformation of bipolar postmigratory Purkinje cells into the stellate cell stage results from a complex cascade of alternating creative and destructive processes, taking place in parallel with the formation and regression of mature synaptic contacts, between the remodelling dendritic arbors and unidentified afferent inputs. Purkinje cells, in all the different transitional stages, are present side by side in the same folial regions, at least until P4, and receive a similar contingent of synaptic input. This indicates that the dendritic remodelling is not driven by the synaptic inputs, but obeys either neural interactions that lead Purkinje cells to assume their monocellular layer configuration, or an internal clock depending on the Purkinje cell birthdate, or an interplay between these two kinds of mechanisms.

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PubMed1991

Relationships between neuronal birthdates and cytoarchitecture in the rat inferior olivary complex.

The correlation between birthdates of neurons and their ultimate location within the inferior olivary nucleus (ION) was investigated in the rat by the 5-bromodeoxyuridine (BrdU) method. We performed injections every 4 hours throughout the ION generation period, and were thus able to demonstrate that 1) neurons are distributed in the adult ION following characteristic gradients that define subdivisions identical to those established by hodological studies; and 2) ION neurons born at the same time tend to be arrayed in small clusters in the adult structure. Implications of these findings for the mechanisms of olivary neuron migration, selective aggregation, and elaboration of projectional topography are discussed. This study provides direct evidence that one of the factors governing the elaboration of the cytoarchitecture of a neuronal nucleus is the temporal sequence of generation of its neurons.

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PubMed1991

Cerebellar development: afferent organization and Purkinje cell heterogeneity.

Olivo- and spinocerebellar maps in the adult cerebellum of small rodents are discontinuous, with sharp boundaries. Cortical Purkinje cells constitute a heterogeneous population, organized into parasagittal, mutually exclusive compartments. The boundaries of the intrinsic cortical compartments and those of the projectional maps are congruent. During development; (i) The incoming olivary fibres, once they penetrate in the cerebellar parenchyma, are attracted toward their ultimate terminal fields, without passing through a stage of random dispersion. (ii) Migrating Purkinje cells and inferior olivary neurons begin, asynchronously, to express cellular markers in an independent manner, giving rise to a transient compartmentation of the cerebellar cortex and the inferior olivary complex respectively. In both instances, the biochemical heterogeneity disappears during the first postnatal week, simultaneously with the acquisition of adult-like cerebellar maps. (iii) The formation of the maps is an early event, prior to the establishment of the synaptology of the cerebellar cortical circuitry. Moreover, the organization of the spinocerebellar projection in adult mutant mice does not depend on the presence of granule cells (staggerer) but on the presence of normal Purkinje cells (weaver), indicating that synaptogenesis with their target neurons is not involved in the process of map formation. The matching of region specific chemical labels between incoming afferent fibres and heterogeneous sets of Purkinje cells is the most appealing mechanism for the formation of cerebellar maps.

Afferent Pathways↗

PubMed1991

Immunohistochemical study of short- and long-term effects of DL-fenfluramine on the serotonergic innervation of the rat hippocampal formation.

Owing to the long-lasting depletion in brain serotonin (5-HT) produced by high doses of the amphetamine derivative DL-fenfluramine, this drug has been suspected of neurotoxicity; the serotonergic innervation of the hippocampal formation being one of its most vulnerable targets. A first series of experiments has been carried out to determine, through a 5-HT immunohistochemical study in the rat, the validity of this claim, as well as the rate and the degree of 5-HT recovery. Five to 12 days after a high intraperitoneal dose of DL-fenfluramine (26.8 mg/kg) there is a profound, increasing reduction in the density of serotonin-immunoreactive (5-HT-IR) axons in all portions of the hippocampal formation. The fine-caliber fibers being more affected than the thicker axons. In parallel with this decrease, numerous 5-HT-IR fibers in the cingulum bundle, fornix-fimbria and the hippocampal parenchyma exhibit structural changes, similar to those produced by 5,7-dihydroxytryptamine, a specific neurotoxin of the 5-HT system. By 20 days after the treatment, abnormal axons have disappeared and the density of 5-HT-IR normal axons is markedly increased. By 40 days, the pattern of 5-HT hippocampal innervation is restored but its density is still lower than in controls. These findings, which corroborate the neurotoxic action of fenfluramine, provide anatomical evidence that the chemical ablation is followed by a slow process of axonal regeneration, started between 12 and 20 days and still uncompleted at 40 days. A second series of experiments, with chronic oral administration of DL-fenfluramine, has been conducted to determine presumptive potentiation through a cumulative effect of the drug, and to analyze the recovery process. One day after the end of the treatment with high dose regimens (210 mg/kg, distributed into 5 mg/kg twice daily for 21 days), together with a marked decrease in the density of 5-HT-IR fibers there are some rare forms of axonal pathology. 15 days later, altered axonal forms have disappeared and the density of 5-HT-IR axons has considerably increased, reaching normal levels by 30 days (56 days after the first exposure to the drug). Hence, despite the ability of the fenfluramine to exert its action on 5-HT axons all over the duration of the treatment, it does not exert a noxious cumulative effect as revealed by the low level of axonal pathology noticeable 22 days after the initiation of the treatment, and the relatively fast and complete recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1991

The reconstruction of cerebellar circuits.

Repair of adult 'point-to-point' systems by neural grafting is possible only when grafted neurons succeed in synaptically replacing the host's missing neurons, thus re-establishing the anatomical and functional integrity of the impaired circuits. Grafting experiments carried out on the cerebellum of the adult pcd (Purkinje-cell-degeneration) mutant mouse (an animal model of hereditary degenerative ataxia) reveal that embryonic Purkinje cells, by some unknown sorting mechanism, selectively invade the deprived cerebellar cortex. These neurons migrate to their proper domains and, inducing axonal sprouting of specific populations of host neurons, they become integrated synaptically within the pcd cerebellar cortex. However, the re-establishment of the corticonuclear projection is achieved only rarely, and this is the current experimental limit for the complete reconstruction of the cerebellar circuit.

Animals↗

PubMed1991

Cerebellar synaptogenesis: mutant mice--neuronal grafting.

Neurological mutations affecting the cerebellum of the mouse have offered the possibility to study some of the cellular mechanisms involved in the establishment of synaptic connections (see in Sotelo, 1990). Indeed, these mutations provoke through well-defined lesions, the disruption of the normal processes of synapse formation and, by examination of the perturbations in the adult cerebellar connectivity, it is possible to unravel some of the numerous and intricate cellular interactions taking place during synaptogenesis. Furthermore, some of these mutants primarily affect Purkinje cells, the pivotal elements of the cerebellar cortex and its only output, inducing their degeneration. These Purkinje cell-deficient cerebella offer an optimal material to try--by grafting experiments--to replace the missing neurons, and to analyze synaptogenic processes between neuronal partners of different biological ages: the host adult neurons and the embryonary grafted Purkinje cells (Sotelo et al., 1990). The aim of this paper is to summarize some of the work carried out in my laboratory concerning the two above-mentioned topics.

Animals↗

PubMed1990

Hot-foot murine mutation: behavioral effects and neuroanatomical alterations.

We have studied the behavior of a new neurological mouse mutant, the hot-foot mutant. The most obvious phenotypic characteristic of the mutation is an abnormality of posture (body flattened on the ground, back limbs spread wide) and of locomotion (backing up and jerky movements of the hind limbs). Neuroanatomical analysis of the cerebellum showed abnormalities mainly related to the Purkinje cells, which have ectopic spines devoid of presynaptic innervations. The correspondence between the cerebellar alterations and the abnormalities of locomotion is thus clearly illustrated. However, the mild degree of the anatomical alterations does not seem sufficient to account for the degree of effect on locomotion and posture.

Animals↗

PubMed1990

Fate of grafted embryonic Purkinje cells in the cerebellum of the adult "Purkinje cell degeneration" mutant mouse. I. Development of reciprocal graft-host interactions.

In this paper, we have morphologically studied the developmental events underlying the neuronal replacement, 3-21 days after grafting. Despite their abnormal environment, Purkinje cell progenitors proceed with their proliferation in the grafted neuroepithelium, with a time window similar to that characterizing proliferation of this neuronal class in control mouse embryos. Only postmitotic Purkinje cells leave the grafts and migrate to the host molecular layer following stereotyped pathways. These neurons invade the host molecular layer, either through a tangential migration under the pial basal lamina from the graft/host interface or breaking locally the latter, and passing directly from the lateral swellings of the graft lying on the surface of the host folia. Whatever the pathway for host invasion, the migrating Purkinje cells penetrate radially and/or obliquely into the host molecular layer until their inward-oriented processes attain the molecular/granular layer interface, which occurs about 7 days after grafting. At the end of their migration, the grafted Purkinje cells with bipolar shapes and long and smooth processes begin to build up their ultimate dendritic trees. This dendritogenesis proceeds with constructive and regressive processes, passing through the same three developmental phases described by Ramón y Cajal (Trab. Lab. Invest. Biol. Univ. Madrid 24:215-251, 1926) for control Purkinje cells (phase of the fusiform cell, phase of the stellate cell with disoriented dendrons, and phase of orientation and flattening of the dendrites). In the grafted cerebella, the duration of the second and third phases is somewhat shorter than during normal cerebellar ontogenesis. Synaptogenesis between adult host axons and grafted Purkinje cells starts when the latter attain their second phase of dendritic development. Somatic filopodia emerging from grafted Purkinje cells begin, 10-11 days after grafting, to be synaptically contacted by axonal sprouts of the host climbing fibers resulting, 2 days later, in the formation of pericellular nests. Synaptogenesis between slender dendritic spines and host parallel fibers, together with that of axon terminals from host molecular layer interneurons and the smooth surface of the grafted Purkinje cell somata, begin earlier than in control mouse development, being almost simultaneous with climbing fiber/Purkinje cell synaptogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Fate of grafted embryonic Purkinje cells in the cerebellum of the adult "Purkinje cell degeneration" mutant mouse. II. Development of synaptic responses: an in vitro study.

Solid pieces of cerebellar primordia from 12-day-old C57Bl embryos were implanted in the cerebellar vermis of 3-4-month-old "Purkinje cell degeneration" mutant mice. Ten to 22 days after grafting, mutant mice were sacrificed, and synaptic responses of grafted Purkinje cells were studied by intracellular recordings performed in 400 microns thick sagittal slices in vitro. As early as 10 days after transplantation, grafted Purkinje cells have already completed their migration from the implant into the host molecular layer. Accordingly, inhibitory as well as excitatory responses were already elicited in these cells by electrical stimulation of the host subcortical white matter. Furthermore, a transient stage of multiple innervation of Purkinje cells by climbing fibers exists between 10 and 15 days after grafting, as revealed by the stepwise variation in amplitude of the climbing fiber-mediated excitatory postsynaptic potentials recorded before 15 days after grafting. Thirteen days after transplantation, typical all-or-none climbing fiber-mediated responses, parallel fiber-mediated excitatory postsynaptic potentials, and inhibitory postsynaptic potentials were also already present. Finally, normal adult-type synaptic responses were observed in all tested cells 15 to 17 days after grafting. Together with the companion paper (Sotelo et al., 1990), these results demonstrate that grafted Purkinje cells are able to impose on host afferents a pattern of synaptogenesis which closely follows that occurring during normal development, in particular, the transient stage of multiple innervation of Purkinje cells by climbing fibers.

Action Potentials↗

PubMed1990

Expression of compartmentation antigen zebrin I in cerebellar transplants.

The mammalian cerebellum is divided into multiple parasagittal compartments as defined by the organization of afferent and efferent projections and by the pattern of expression of several biochemical markers. One such marker is the antigen zebrin I, a 120 kD polypeptide of unknown function that is expressed differentially by a subset of Purkinje cells. Zebrin I+ Purkinje cells are grouped into an array of 14 parasagittal bands interposed by zebrin I- compartments. This Purkinje cell compartmentation corresponds to compartments in the olivocerebellar projection. The afferent axon compartments are present prior to the expression of the mature zebrin I phenotype, thus raising the possibility that differential afferent input regulates the zebrin I phenotype of the target of that input. Lesion studies in the neonate preclude a role for afferent inputs in the regulation of zebrin I expression postnatally, but a prenatal role in commitment still remains open. To explore this possibility, cerebellar anlagen were dissected from embryos at embryonic days 12-15, that is, prior to any contact with afferents, and transplanted ectopically into adult hosts. In the first series of experiments, the grafts were placed into the anterior chamber of the eye, and in the second series, into cavities prepared in the neocortex. Grafts were allowed to mature and then were immunoperoxidase or immunofluorescence stained for zebrin I immunoreactivity. Zebrin I was expressed by grafted Purkinje cells in cortico and in oculo. Double-labelling experiments confirmed that both the zebrin I+ and the zebrin I- phenotypes were present. The zebrin I immunoreactivity revealed that the zebrin I+ Purkinje cells resemble those in situ with an extensive dendritic arborization that extends through the molecular layer perpendicular to the long axes of the folia. In conclusion, the present data suggest that afferent input does not play a role in the determination of the zebrin I phenotype of Purkinje cells.

Animals↗

PubMed1990

Migratory pathways and selective aggregation of the lateral reticular neurons in the rat embryo: a horseradish peroxidase in vitro study, with special reference to migration patterns of the precerebellar nuclei.

The migration and ultimate domain invasion of postmitotic lateral reticular nucleus (LRN) neurons were followed in embryonic day 15-20 (E15-E20) rat embryos, by using a horseradish peroxidase (HRP) in vitro axonal tracing method. All of the LRN axons elongate and neuronal somata migrate via the subpial or marginal migratory stream (mms), circumnavigating the ventrolateral aspect of the medulla at the glial endfeet level. They reach the ventral midline at E16, bypass it, and begin to settle in their final territory at E17. At E18 the LRN anlage is fully formed, and at E19-E20 its cells have finished their migration and are rapidly differentiating. Comparison of these sequential steps with their counterparts in the development of the inferior olive (ION) and external cuneatus (ECN) brings to light the essential role of the neuroepithelial cells of the interolivary commissure (the "floor plate"). This zone is likely to act as 1) a chemoattractant for the growth cones of the LRN, ION, and ECN, and 2) a decision-making center, which instructs the somata of these neurons to cross the midline or not, ultimately governing the crossed or uncrossed pattern of their projection to their common target, the cerebellum. Finally, the ontogeny of the LRN and ECN provides a most surprising example, even unique in the central nervous system, of long-distance, neurophilic migration that conveys neuronal cell bodies contralaterally to the side on which they proliferate.

Animals↗

PubMed1990

Grafts of dissociated cerebellar cells containing Purkinje cell precursors organize into zebrin I defined compartments.

A prominent feature of the mammalian cerebellum is its organization into parasagittal compartments. One marker of such compartments is the zebrin I molecule that is expressed by bands of Purkinje cells (PC). In order to understand better the basis for the development of this organization, we have transplanted dissociated rat cerebellar anlage, taken during the period of proliferation of PC precursors, into kainic acid lesioned adult rat cerebellum. As previously observed, the resultant grafts exhibited trilaminar structures reminiscent of the normal cerebellum. In every case, the PC in the resultant grafts were organized into zebrin I+ and - compartments. In one case, most of the grafted PC were integrated into a region of PC deficient host molecular layer that was induced by pretreatment with kainic acid. Clear bands defined by zebrin I reactivity were seen where groups of the grafted PC had entered the host molecular layer. These bands did not correlate in distribution or size with host bands. Hypotheses compatible with these findings that involve specific and non-specific aggregation of PC are discussed.

Animals↗

PubMed1990

Axonal abnormalities in cerebellar Purkinje cells of the 'hyperspiny Purkinje cell' mutant mouse.

The hyperspiny Purkinje cell (hpc) is a murine, autosomal recessive mutation affecting cerebellar Purkinje cells. Axonal abnormalities in these neurons have been revealed by selective silver impregnation, specific immunohistochemical staining and electron microscopy. The main pathological feature consists of a massive axonal degeneration in the terminal domains of the Purkinje cell projection. This process starts approximately ten days postnatally, simultaneously with the onset of cerebellar symptoms, and evolves very rapidly. By 21 days, the vast majority of the terminal arbors have degenerated, resulting in an almost complete disruption of the corticonuclear projection. Axonal degeneration, although proceeding in a dying-back fashion, only provokes retrograde death in a small percentage of Purkinje cells (less than 15%). Purkinje cells exhibit other signs of axonal damage and axonal reaction: (a) Almost all of them bear gigantic varicosities (spheroids or torpedoes) along their transit through the granular layer. (b) In a small percentage of cases, a dendritic segment is inserted between the axon hillock and the initial segment (meganeurite). These ectopic dendrites receive a normal contingent of synaptic inputs, and are transient structures observed in four- to six-week-old mice. (c) The infra- and supraganglionic plexuses, formed by recurrent collaterals of Purkinje cell axons, have increased density and terminal domains. (d) In mice aged over 50 days, many Purkinje cells have developed 'arciform' axons, which is evidence of a compensatory reaction. The definite axonal pathology of hpc Purkinje cells confers to this mutation its own specificity, which differs from all other known mutations primarily affecting this neuronal population. Therefore, the hpc mutation offers a valuable tool to analyse some of the genetic factors involved in the differentiation and maintenance of cerebellar Purkinje cells.

Animals↗

PubMed1990

Cerebellar synaptogenesis: what we can learn from mutant mice.

Examination of perturbations in the adult cerebellar connectivity, that follow well-defined lesions produced by gene mutations in the mouse, reveals a few of the numerous and intricate cellular interactions taking place during synaptogenesis. In weaver and in the central ectopia of reeler, Purkinje cells form innumerable dendritic spines, despite the absence of parallel fibers. Only a small proportion of these spines are innervated, and their presynaptic partners are mossy fibers (heterologous synapses) originating from spinal cord, but not from pontine nuclei. Hence, the early phase of membrane recognition is based more on a hierarchical choice between a wide range of graded preferences, than on the complementarity of a narrow range of synaptic affinities. The comparative analysis of weaver, reeler, staggerer and hyperspiny Purkinje cell has allowed us to establish that the late phase of synapse stabilization or elimination, leading to the numerical matching of one climbing fiber per Purkinje cell, is not based on climbing fiber translocation. Conversely, this regression appears to be the result of a process of competition between climbing fibers and parallel fibers. Whatever the mechanisms of the competition are, the results obtained with the mutants suggest that activity of the forming cerebellar circuitry is involved in their regulation. Finally, a new mutation is reported, the nodding mouse, to illustrate the fact that the ultimate morphology of presynaptic boutons results from an interplay between intrinsically regulated factors (features of presynaptic organelles) and the morphogenetic influence of postsynaptic partners. This accounts for the size and shape of the boutons as well as for the class of synaptic junction. Furthermore, this morphogenetic influence is not restricted to early life but occurs whenever the originally established balance between pre- and postsynaptic elements is upset.

Animals↗