Interneurons of the hippocampus

Early clinical observations and recent systematic studies overwhelmingly document a greater role for psychosocial stressors in association with the first episode of major affective disorder than with subsequent episodes. The author postulates that both sensitization to stressors and episode sensitization occur and become encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episodes themselves can induce the protooncogene c-fos and related transcription factors, which then affect the expression of transmitters, receptors, and neuropeptides that alter responsivity in a long-lasting fashion. Thus, both stressors and episodes may leave residual traces and vulnerabilities to further occurrences of affective illness. These data and concepts suggest that the biochemical and anatomical substrates underlying the affective disorders evolve over time as a function of recurrences, as does pharmacological responsivity. This formulation highlights the critical importance of early intervention in the illness in order to prevent malignant transformation to rapid cycling, spontaneous episodes, and refractoriness to drug treatment.

Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.

Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

Experience-dependent structural synaptic plasticity in the mammalian brain.

Chronic stress produces structural changes and neuronal damage especially in the hippocampus. Because neurotrophic factors affect neuron survival, we questioned whether they might be relevant to the heightened vulnerability of hippocampal neurons following stress. To begin investigating this possibility, we examined the effects of immobilization stress (2 hr/d) on the expression of neurotrophic factors in rat brains using in situ hybridization. We found that single or repeated immobilization markedly reduced brain-derived neurotrophic factor (BDNF) mRNA levels in the dentate gyrus and hippocampus. In contrast, NT-3 mRNA levels were increased in the dentate gyrus and hippocampus in response to repeated but not acute stress. Stress did not affect the expression of neurotrophin-4, or tyrosine receptor kinases (trkB or C). Corticosterone negative feedback may have contributed in part to the stress-induced decreases in BDNF mRNA levels, but stress still decreased BDNF in the dentate gyrus in adrenalectomized rats suggesting that additional components of the stress response must also contribute to the observed changes in BDNF. However, corticosterone-mediated increases in NT-3 mRNA expression appeared to be primarily responsible for the effects of stress on NT-3. These findings demonstrate that BDNF and NT-3 are stress-responsive genes and raise the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus.

https://www.jneurosci.org/content/jneuro/15/3/1768.full.pdf

Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus

The cytology of the postmitotic migratory granule cell and its relationship to Bergmann glial processes was examined with Golgi staining and electron microscopy in the three cardinal planes in the developing cerebellar cortex of Macacus rhesus at various late fetal and early postnatal ages. After final mitosis the granule cell body transforms from a nearly round shape in the superficial zone of the external granular layer to a horizontal bipolar form with elongated processes oriented longitudinally to the folium, at the outer border of the molecular layer. Another descending process develops, and the cell soma becomes a pyramid flattened in the plane longitudinal to the folium. The nucleus moves into the descending process and the cell soma assumes a vertically oriented spindle shape while migrating among previously formed parallel fibers deeper in the molecular layer, and finally attains a round shape again when it lies deep to the Purkinje cell layer. During these transformations, the cell cytoplasm becomes more voluminous and contains a prominent Golgi apparatus, numerous free ribosomes, mitochondria, multivesicular and dense bodies, and fascicles of microtubules Longitudinally oriented microtubules concentrated in the vertical leading process disappear by the time the cell soma enters the granular layer. The slender trailing process loss most of its cytoplasmic organelles, acquires microtubules and together with the horizontal processes forms the characteristic T-shaped axon. The axon forms synapses with Purkinje and stellate cell dendrites at a time when other granule cells are still migrating among them.

During the entire course of their migration across the molecular layer, granule cells are directly apposed to vertically oriented Bergmann fibers belonging to the Golgi epithelial cells. The sequence of developmental stages indicates that Golgi epithelial cells are a type of protoplasmic astrocyte. The Bergmann fibers were present at all stages examined, and their constant apposition to granule cells suggests a role in the lartter's migration. Numerous electronluscent beady enlargements are seen along the fiber except at sites were the surface is in contact with migrating cells; probably these enlargements change position as the granule cells pass along the Bergmann fiber. Lamellate expansions also project from the main shaft of the glial fiber and envelop the synaptic sites on spines of Purkinje cell dendrites. These expansions seem more durable, and the young neuron appears to avoid collision with them by sprialling around the glial shaft during its descent to the granular layer. The neuron-glia relationship apparently provides the necessary conditions for the migration of the young granule cell. Especially at late developmental stages when the molecular layer is more than 250 μ wide and is densely packed with highly oriented cell processes that have already established synaptic connections.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cne.901410303

Neuron‐glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electonmicroscopic study in Macacus rhesus

Abnormal functional activity induces long-lasting physiological alterations in neural pathways that may play a role in the development of epilepsy. The cellular mechanisms of these alterations are not well understood. One hypothesis is that abnormal activity causes structural reorganization of neural pathways and promotes epileptogenesis. This report provides morphological evidence that synchronous perforant path activation and kindling of limbic pathways induce axonal growth and synaptic reorganization in the hippocampus, in the absence of overt morphological damage. The results show a previously unrecognized anatomic plasticity associated with synchronous activity and development of epileptic seizures in neural pathways.

https://science.sciencemag.org/content/sci/239/4844/1147.full.pdf

Synaptic reorganization in the hippocampus induced by abnormal functional activity.

The relationship of the climbing fibers to developing Purkinje cells in the cerebellums of fetal macaques at 75-, 100-, 125-, and 150-days after conception was studied using Golgi stains and electron microscopic techniques. Between 125 and 150 days of fetal life the somatic processes of the Purkinje cells were most prominent and the apical dendrites were in the initial stages of their development. Serial sections of Purkinje cells, in the cerebellums of 125-day fetuses, were made and photographed in the electron microscope. Montages of individual Purkinje cells were prepared to permit tracing of the somatic processes and the climbing fibers. It was observed that Purkinje cells developed processes only after becoming associated with climbing fibers and that the climbing fiber terminals capped the growing ends of the processes at this critical stage. In several cases, growing tips of these processes penetrated the terminal boutons. The fine structure of the synaptic junction between the climbing fiber terminal and the Purkinje cell was analyzed using stereo-electron micrographs (× 125,000). From these observations and those of other authors it was concluded that the climbing fiber induces the formation of somatic processes which then develop into the elaborate dendritic tree. Furthermore, it is proposed that synaptic connections have contractile properties, and that it is this contractility which induces dendrite elaboration.

The role of climbing fibers in the formation of Purkinje cell dendrites.

Albino mammals have abnormal visual pathways "Flecked" mice have a variegated pigment distribution, with roughly half the cells normally pigmented and half albino They do not show the albino abnormality in the visual pathways The gene at the albino locus, which determines the course of the visual pathways must, thus, have an extracellular action

https://science.sciencemag.org/content/sci/179/4077/1014.full.pdf

Genetic Mechanisms Determining the Central Visual Pathways of Mice

Although the influence of electrical activity on neural development has been studied extensively, experiments have only recently focused on the role of activity in the development of the mammalian central nervous system (CNS). Using tetrodotoxin (TTX) to abolish sodium-mediated action potentials, studies on the visual system show that impulse activity is essential both for the normal development of neuronal size and responsivity in the lateral geniculate nucleus (LGN), and for the eye-specific segregation of geniculo-cortical axons. There have been no anatomical studies to investigate the influence of action potentials on CNS synaptic development. We report here the first direct evidence that elimination of action potentials in the mammalian CNS blocks the growth of developing axon terminals and the formation of normal adult synaptic patterns. Our results show that when TTX is used to eliminate retinal ganglion-cell action potentials in the cat from birth to 8 weeks, the connections made by ganglion cell axons with LGN neurones, retinogeniculate synapses, remain almost identical morphologically to those in the newborn kitten.

Elimination of action potentials blocks the structural development of retinogeniculate synapses.

The development of glial and synaptic relations has been studied in long term cultures of spinal cord by light and electron microscopy.



During the first three days in vitro there is extensive cell death in the superficial parts of the explants, where one sees many phagocytes and much cellular debris. The ependyma of the explants early forms a closed sac in the deep parts of the culture next to the collagen substrate. Cells migrate from this sac to form a continuous basal layer upon the substrate. Some of these cells turn around the edges of the explant and migrate onto its surface, where they contribute to an ependyma-like epithelial covering. As the explants mature most of the cellular debris is cleared; the epithelial covering separates the neuronal elements from the feeding solution and from phagocytes, most of which migrate to lie freely on the surface of the epithelium.



Two types of outgrowth are formed. The first consists of bundles of nerve fibers which are accompanied by individual undifferentiated glial cells. The second forms as a broad sheet of undifferentiated glial cells and astrocytes and this is continuous, at the edge of the explant, with the glia of the basal layer. Nerve fibers that grow into this sheet appear to survive better than nerve fibers that grow out in bundles. Oligodendroglial cells become recognizable by electron microscopical criteria when the axons start to myelinate.



Dendrites can be identified in the sheet-like outgrowth but not in the bundles. Synapses are seen only where dendrites are identifiable. Serial axo-axonal junctions have not been found and axosomatic synapses are relatively rare.

Grayson Scott

Papers

Synaptic reorganization in the hippocampus induced by abnormal functional activity.

The role of climbing fibers in the formation of Purkinje cell dendrites.

Genetic Mechanisms Determining the Central Visual Pathways of Mice

Elimination of action potentials blocks the structural development of retinogeniculate synapses.

Relationships between glial and neuronal elements in the development of long term cultures of the spinal cord of the fetal mouse