Reduction In Synaptic Density Research Articles

Lysosomal Dysfunction Produces Distinct Alterations in Synaptic α-Amino-3-Hydroxy-5-Methylisoxazolepropionic Acid and N-Methyl-D-Aspartate Receptor Currents in Hippocampus

The early processes that lead to synaptic dysfunction during aging are not clearly understood. Dysregulation of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors may cause age-related cognitive decline. Using hippocampal slice cultures exhibiting lysosomal dysfunction, an early marker of brain aging that is linked to protein accumulation, we identified alterations to AMPA and NMDA receptor-mediated synaptic currents. The miniature and spontaneous excitatory postsynaptic currents that were examined after 3, 6, and 9 days of lysosomal disruption showed progressive changes in amplitude, frequency, and rise and decay kinetics. To investigate whether modifications in specific channel properties of single synaptic receptors contributed to changes in the amplitude and time course of synaptic currents, we examined the single channel properties of synaptic AMPA and NMDA receptors. The channel open probability and the mean open times showed decreases in both receptor populations, whereas the closed times were increased without any change in the channel conductance. The Western blot analysis revealed a progressive decline in synaptic markers including glutamate receptor subunits. These results indicate that lysosomal dysfunction leads to progressive functional perturbation of AMPA and NMDA receptors in this slice model of protein accumulation, suggesting that age-related cognitive decline could result from altered glutamate receptor function before reductions in synaptic density.

Induction of Serine Racemase Expression and D-Serine Release from Microglia by Secreted Amyloid Precursor Protein (sAPP)

Alzheimer's disease (AD) involves neuronal loss and reduction of synaptic density in specific brain region. Some of the neuronal deaths are associated with excitotoxicity. We previously reported that amyloid beta-peptide (Abeta) induced release of N-methyl-D-aspartate receptor (NMDA-R) co-agonists, including glutamate and D-serine. The induction of D-serine production by Abeta involves transcriptional and/or translational regulation of serine racemase gene. Similarly, we report here that conditioned medium from microglia treated with secreted amyloid precursor protein (sAPP) contained elevated levels of D-serine. In microglia, sAPP increased the steady-state dimeric protein level of serine racemase. Promoter-reporter and mRNA analyses suggested that serine racemase is transcriptionally induced by sAPP. These data extend the link between excitotoxicity and neuroinflammation. D-serine may cooperate with glutamate to link neuroinflammation with excitotoxicity, suggesting a pathogenic mechanism applicable to neuronal death in AD and other neurodegenerative diseases.

Functional activation of cerebral metabolism in mice with mutated thyroid hormone nuclear receptors.

Neonatal hypothyroidism impairs structural maturation in the brain and results in diminished electrical activities and energy metabolism. We recently found that glucose utilization (CMR(glc)) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor alpha1 (TR alpha 1), but not TR beta. Previous studies had shown that CMR(glc) increases linearly with spike frequency in the afferent pathways to synapse-rich regions in neuropil, but not in neuronal cell bodies. To determine whether the decreased CMR(glc) in mutant TR alpha 1(PV/+) mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMR(glc) bilaterally in four stations of the whisker-to-barrel cortex pathway. Baseline CMR(glc) (unstimulated side) was markedly lower in all four stations in the TR alpha 1(PV/+) mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na(+),K(+)-adenosine triphosphatase expression and neuronal differentiation. Despite the lower baseline CMR(glc), however, vibrissal stimulation evoked percent increases in CMR(glc) in the TR alpha 1(PV/+) mutants that were as great as those in wild-type mice. These results indicate that in the TR alpha 1(PV/+) mutants there it is a reduction in synaptic density that is responsible for the decrease in CMR(glc), but functionality of existing synapses is retained.

Synaptic density of the prefrontal cortex regulated by dopamine instead of serotonin in rats

Recent findings indicate that monoamine contributes to synaptic plasticity. We examined the synaptic density of the prefrontal cortex and parietal cortex of rats using dopamine (DA) antagonists and agonists, as well as serotonin (5-HT) depleters and found a reduction in synaptic density in the prefrontal cortex lamina V–VI at a maximum of 20% with administration of a D 1 antagonist (SCH23390) and at a maximum of 30% with a D 2 antagonist (YM09151). Further, with the administration of D 1+D 2 antagonists there was a 27% decrease in synaptic density, which was a larger reduction than the total of the single dosages of each DA antagonist at equal levels. Increase in synaptic density was seen at a maximum of 8.5% with dosage of a D 1 agonist (SKF38390) and 14.5% with dosage of a D 2 agonist (PPHT). The dosage of D 1+D 2 agonists showed a 27.1% increase in synaptic density. There was no change in synaptic density of the parietal cortex with either DA antagonist or agonist administration. Administration of 5-HT depleter pCPA resulted in a 13.8% reduction of synaptic density in the parietal cortex, though there was no change identified in the synaptic density in the prefrontal cortex. Based on these results, it was suggested that the area of the brain with affected synaptic plasticity could differ, depending on the type of monoamine.

Retardation in water maze learning not by loss of LTP but by reduction of synaptic density

Retardation in water maze learning not by loss of LTP but by reduction of synaptic density

2213 Retardation in water maze learning not by loss of LTP but by reduction of synaptic density

2213 Retardation in water maze learning not by loss of LTP but by reduction of synaptic density

Synaptophysin immunoreactivity is stable 36 h postmortem.

The effects of postmortem time, age and tissue storage time on synaptic density were investigated in the prefrontal cortex of human brains. Thirty normal cases and 10 patients with a variety of neurologic diseases were studied, using quantitative immunohistochemistry with a monoclonal antibody to synaptophysin. Synaptophysin immunoreactivity was stable during the first 36 h after death, showing no significant change at 1, 8, 12, 24 and 36 h postmortem in normals. However, at 48 and 72 h postmortem, synaptophysin immunoreactivity decreased significantly. A similar pattern of postmortem changes was found in the disease group. In 14 normal cases with a wide range of ages, a significant reduction in synaptic density with age was observed while the time of tissue storage as paraffin-embedded blocks had no significant effect on the synaptophysin immunoreactivity. These results support the validity of using synaptophysin immunohistochemistry as a measure of synaptic density in human brain autopsied within 36 h of death and stored as paraffin-embedded blocks for a long time.

Changes in synaptic density after developmental compression or expansion of retinal input to the superior colliculus

The retinal projection to the superior colliculus can be made abnormally dense by inducing a "compressed" retinal projection into a subnormal tectal volume, or abnormally sparse by monocular enucleation early in development. Any or all of the features of cell number, axonal arbor, dendritic arbor, and synaptic density could potentially be adjusted to compensate for such variations in the convergence of one cell population on another. We have examined the consequences of neonatal partial tectal ablation or monocular enucleation for synaptic length, density, and relative numbers of synapse classes in the superficial gray layer of the hamster superior colliculus. Monocular enucleation resulted in a reduction of synaptic density in the superficial gray layer of the colliculus ipsilateral to the remaining eye. This decrease in density was entirely accounted for by a reduction of the number of synapses with round vesicles, large asymmetric terminal specializations, and pale mitochondria characteristic of retinocollicular terminals (RLP synapses). There was no compensatory increase in any other synaptic class. RLP synapses were larger in monocular enucleates. Partial tectal ablation had no effect on synaptic density, nor on the relative proportions of different synaptic types. Synapses of the RLP class were slightly smaller than normal. These results suggest that synaptic density is normally at a maximum that cannot be altered by increases in potential input. However, density may be reduced by decreasing the number of inputs. Terminal classes do not appear to compete with each other within the collicular volume, suggesting that postsynaptic cells controls both the classes and numbers of their potential inputs.

Mechanisms of Amyloid Deposition in Alzheimer's Diseasea

At the cellular level, Alzheimer's disease (AD) must be the result of neuronal dysfunction and degeneration leading to a reduction in synaptic density. Filamentous deposits of amyloid, which define the disease at the molecular level, occur within perikarya, axons, dendrites, and terminals of neurons as neurofibrillary tangles (NFT), in the extracellular neuropil as amyloid plaques (APC), and around blood vessels as amyloid congophilic angiopathy (ACA). These fibrillar amyloid protein aggregates are also found in the brain of all individuals with Down's syndrome after the age of 30 years. The amyloid deposits apparently occur in the terminal zones of neurons that develop NFT. It is suggested that amyloid deposition is of fundamental significance in AD and that a thorough understanding of amyloid formation will eventually lead to successful therapeutic intervention in AD. As elucidation of the reasons behind amyloid deposition must shed some light on the pathogenesis of AD, we review the current state of knowledge on the nature of the AD amyloid protein, its origin, and its formation. Although there is yet no agreement about the chemical nature of the amyloid protein of NFT, the major constituent of both APC and ACA has been shown to be a 4.5-kD amyloid protein originally termed "beta-protein" or "amyloid A4" which we now denote as "beta A4." Amyloid beta A4 protein is proteolytically derived from a transmembrane protein termed amyloid precursor protein (APP) which is encoded by a widely expressed gene on chromosome 21. Our present results are consistent with the possibility that amyloid formation requires membrane damage or APP molecules that are not or are incorrectly integrated into membranes. To allow the generation of the C-terminus of beta A4, one proteolytic cleavage step has to occur in the sequence that normally forms the transmembrane domain of the APP proteins. This cleavage is crucial for amyloid formation because we could show that the ability of synthetic beta A4 to form amyloid depositions is mainly based on hydrophobic parts of the sequence that have to interact with each other and build up large aggregates under physiologic conditions. Membrane association of APP is expected to interfere with this cleavage and the process of aggregation.

A quantitative analysis of the synaptic development of the lobus parolfactorius of the chick (Gallus domesticus).

The lobus parolfactorius (LPO) of the chick has been shown to undergo an increase in the mean synaptic numerical density (Nvsyn) in response to one-trial passive avoidance learning (Stewart et al. 1987). The present study was undertaken in order to describe the pattern of normal development of synapses in the LPO, to further investigate the significance of this plastic response. The LPO's from each hemisphere of pre-hatch (16 days), and post-hatch (1 day, 9 day and 22 day old) chicks were processed for electron microscopy. Synapses were classified into asymmetric spine, asymmetric shaft, symmetric spine, and symmetric shaft synapses, on the basis of the density of the post-synaptic thickening and the nature of the post-synaptic target. A 3-dimensional stereological probe was used (the 'disector') to calculate Nvsyn, and mean projected height (Hsyn) of the post-synaptic density (PSD). Mean values for each age and hemisphere were compared with a 2-way analysis of variance test using paired samples. A six-fold increase in Nvsyn was seen between 16 days in ovo, and 9 days post-hatch. There was a hemispheric asymmetry at 9 days post-hatch, with the left hemisphere LPO containing 1.6 times as many synapses per micron-3. There was a subsequent period of reduction in synaptic density in the left hemisphere LPO between 9 and 22 days post-hatch. The Nv of all classes of synapse increased with age, but the proportions of the symmetrical synapses with respect to the total number of synapses, decreased with age. This decrease was of a similar magnitude for each hemisphere. A hemispheric difference was seen in post-hatch asymmetric synapses, with a greater proportion of asymmetric spine synapses in the left hemisphere. The magnitude of the hemispheric asymmetry was constant throughout the 3 week period of post-hatch development, but was not present in pre-hatch chicks. The PSD increased in length in each hemisphere by approximately 40% between post-hatch day 1 and post-hatch day 9. These data show that the LPO contains a synaptic population which undergoes substantial modification during the first week post-hatch. An asymmetry exists at post-hatch day 9 which is not present at the earlier ages investigated, nor indeed after 22 days post-hatch. This may have significance with regard to studies of passive avoidance learning in the one-day old chick, where an increase in both the size and number of synapses in the LPO has been demonstrated (Stewart et al. 1987).(ABSTRACT TRUNCATED AT 400 WORDS)

Cortical pruning and the development of schizophrenia: a computer model.

Schizophrenic patients tend to demonstrate reduced cerebral metabolism in frontal areas. Studies of human brain development reveal that synapses in the cerebral cortex are progressively reduced throughout childhood and adolescence, with parallel reductions in cerebral metabolism. This relationship is not surprising, since synaptic density is a primary factor determining regional metabolic requirements. The elimination of synapses in prefrontal cortex continues for a particularly long period of time, extending well into adolescence. Thus, reduced frontal metabolism in schizophrenic patients could be due to a developmental process--namely, elimination of synapses--gone too far. Animal studies indicate that developmentally induced reductions in synaptic density are due to the pruning of axonal collaterals rather than the death of neurons, which raises a critical question: Does excessive axonal pruning have specific pathological effects on cortical information processing? To answer this question, computer simulations of neural information processing systems were subjected to axonal pruning which reduced synaptic density. If pruning was conducted overzealously, cognitive pathology was induced that could, in humans, lead to the conscious experience of hallucinations, delusions, and Schneiderian symptoms.

The effect of space radiation of the nervous system

The long-term effects of irradiation by accelerated heavy ions on the structure and function of the nervous system have not been studied extensively. Although the adult brain is relatively resistant to low LET radiation, cellular studies indicate that individual heavy ions can produce serious membrane lesions and multiple chromatin breaks. Capillary hemorrhages may follow high LET particle irradiation of the developing brain as high RBE effects. Evidence has been accumulating that the glial system and blood-brain barrier (BBB) are relatively sensitive to injury by ionizing radiation. While DNA repair is active in neural systems, it may be assumed that a significant portion of this molecular process is misrepair. Since the expression of cell lethality usually requires cell division, and nerve cells have an extremely low rate of division, it is possible that some of the characteristic changes of premature aging may represent a delayed effect of chromatin misrepair in brain. Altered microcirculation, decreased local metabolism, entanglement and reduction in synaptic density, premature loss of neurons, myelin degeneration, and glial proliferation are late signs of such injuries. HZE particles are very efficient in producing carcinogenic cell transformation, reaching a peak for iron particles. The promotion of viral transformation is also efficient up to an energy transfer of approximately 300 keV/micron. The RBE for carcinogenesis in nerve tissues remains unknown. On the basis of available information concerning HZE particle flux in interplanetary space, only general estimates of the magnitude of the effects of long-term spaceflight on some nervous system parameters may be constructed.