Decline In Synaptic Density Research Articles

Varying Dietary Component Ratios and Lingonberry Supplementation May Affect the Hippocampal Structure of ApoE-/- Mice.

ObjectiveThis study aimed to investigate and compare the morphological and biochemical characteristics of the hippocampus and the spatial memory of young adult ApoE–/– mice on a standard chow diet, a low-fat diet (LFD), a high-fat diet (HFD), and an HFD supplemented with lingonberries.MethodsEight-week-old ApoE–/– males were divided into five groups fed standard chow (Control), an LFD (LF), an HFD (HF), and an HFD supplemented with whole lingonberries (HF+WhLB) or the insoluble fraction of lingonberries (HF+InsLB) for 8 weeks. The hippocampal cellular structure was evaluated using light microscopy and immunohistochemistry; biochemical analysis and T-maze test were also performed. Structural synaptic plasticity was assessed using electron microscopy.ResultsApoE–/– mice fed an LFD expressed a reduction in the number of intact CA1 pyramidal neurons compared with HF+InsLB animals and the 1.6–3.8-fold higher density of hyperchromic (damaged) hippocampal neurons relative to other groups. The LF group had also morphological and biochemical indications of astrogliosis. Meanwhile, both LFD- and HFD-fed mice demonstrated moderate microglial activation and a decline in synaptic density. The consumption of lingonberry supplements significantly reduced the microglia cell area, elevated the total number of synapses and multiple synapses, and increased postsynaptic density length in the hippocampus of ApoE–/– mice, as compared to an LFD and an HFD without lingonberries.ConclusionOur results suggest that, in contrast to the inclusion of fats in a diet, increased starch amount (an LFD) and reduction of dietary fiber (an LFD/HFD) might be unfavorable for the hippocampal structure of young adult (16-week-old) male ApoE–/– mice. Lingonberries and their insoluble fraction seem to provide a neuroprotective effect on altered synaptic plasticity in ApoE–/– animals. Observed morphological changes in the hippocampus did not result in notable spatial memory decline.

Decision Making Improves Across Adolescent Development in the Rat: Implications for Orbitofrontal Circuit Development

One of the most dynamic phases of brain development occurs during adolescence, the period between birth and adulthood, and is associated with a decline in synaptic density, an increase in myelination and a strengthening of neural circuits. This refinement in neural systems is believed to improve the efficiency of the brain and enhance the speed of information flow across neural networks that are critical for decision-making. The neurobiology that mediate these changes, however, are unknown.

Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment.

Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer's disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood-brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease (AD).

S21-4. Neuropathological hypothesis of sleep dysfunction in Schizophrenia

The purpose of this lecture is to review the polysomnographic non-rapid eye movement sleep abnormalities in schizophrenic patients and to present evidence for possible pathophysiologic mechanisms. Deficits of delta wave sleep are commonly reported sleep architecture abnormalities in schizophrenia. In the1960’s, Feinberg described this abnormality and about twenty years later, he first proposed that a decline in synaptic density resulting from abnormal reorganization of brain structure during early adolescence might cause the decline in delta wave amplitude and the onset of schizophrenia. Recent neuropathological studies of schizophrenia revealed that the dendritic spine density was particularly reduced in layer three of the neocortex. And excessive spine pruning is now considered a potential factor underlying reduced cortical gray matter volume in schizophrenia. Aberrant neuronal pruning is also believed to contribute to compromise the thalamocortical circuitry. Several recent studies have reported markedly reduced sleep spindle activity mediated by thalamocortical circuits in schizophrenia. Animal studies have reported sleep spindles have been linked to synaptic plasticity and memory consolidation. Thus, aberrant pruning can result in structural brain abnormalities and deficits of two distinct rhythms during sleep. Furthermore, each of these impairments appears to be associated with both cognitive deficits and symptoms of schizophrenia.

Impaired extinction retention in adolescent rats: effects of D-cycloserine.

The developmental trajectory of the prefrontal cortex (PFC) in both rats and humans is nonlinear, with a notable decline in synaptic density during adolescence, potentially creating a 'natural lesion' preparation at this age. Given that the PFC is critically involved in retention of extinction of learned fear in adult humans and rodents, the present study examined whether adolescent rats exhibit impaired extinction retention. The results of experiment 1 showed that adolescent rats were impaired in extinction retention, compared with both younger and older rats. The partial NMDA receptor agonist D-cycloserine (DCS) improved extinction retention in adolescent rats (experiment 2), but only if administered immediately after extinction training (experiment 3). In addition, providing extended extinction training improved extinction retention in adolescent rats in a manner similar to that of DCS (experiment 4). The results of this study show that adolescent rats exhibit impaired extinction retention, and that this can be reduced through either DCS or extended extinction training. These novel findings have potential implications for clinical treatments of fear and anxiety disorders in adolescent patients.

Synaptophysin protein and mRNA expression in the human hippocampal formation from birth to old age

In the human neocortex, progressive synaptogenesis in early postnatal life is followed by a decline in synaptic density, then stability from adolescence until middle age. No comparable data are available in the hippocampus. In this study, the integral synaptic vesicle protein synaptophysin, measured immunoautoradiographically, was used as an index of synaptic terminal abundance in the hippocampal formation of 37 subjects from 5 weeks to 86 yr old, divided into 4 age groups (10 infants, 15 adolescents/young adults, 6 adults, and 6 elderly). In all hippocampal subfields, synaptophysin was lowest in infancy, but did not differ significantly between the older age groups, except in dentate gyrus (DG) where the rise was delayed until adulthood. A similar developmental profile was found in the rat hippocampus. We also measured synaptophysin mRNA in the human subjects and found no age-related changes, except in parahippocampal gyrus wherein the mRNA declined from infancy to adolescence, and again in old age. The synaptophysin protein data demonstrate a significant presynaptic component to human postnatal hippocampal development. In so far as synaptophysin abundance reflects synaptic density, the findings support an increase in hippocampal and parahippocampal synapse formation during early childhood, but provide no evidence for adolescent synaptic pruning. The mRNA data indicate that the maturational increases in synaptophysin protein are either translational rather than transcriptional in origin, or else are secondary to mRNA increases in neurons, the cell bodies of which lie outside the hippocampal formation.

Association between protease-specific proteolytic cleavage of brevican and synaptic loss in the dentate gyrus of kainate-treated rats

Proteolytic fragments generated by ADAMTS ( a d isintegrin a nd m etalloprotease with t hrombo s pondin motifs)-mediated cleavage of the aggregating chondroitin sulfate proteoglycan, brevican, have been identified, but not localized in the CNS. The purpose of this study, using kainate-induced CNS lesion, was to examine the spatial and quantitative relationship between ADAMTS1 and 4 mRNA expression and ADAMTS-mediated cleavage of brevican (as determined by the abundance of the neo-epitope QEAVESE at the C-terminal of the cleaved brevican G1 domain). In untreated rats, in situ hybridization and reverse transcriptase polymerase chain reaction indicated that ADAMTS4 expression was higher than ADAMTS1 and was localized to hippocampus, temporal lobe and other areas of cortex, striatum and hypothalamus. ADAMTS4 mRNA expression in these regions correlated with the presence of the QEAVESE neo-epitope, which was concentrated in perineuronal nets and in neuropil. In rats that seized after kainate, there was a dramatic elevation in ADAMTS1 and ADAMTS4 transcript that correlated and co-localized with a robust elevation in an extractable, 55-kDa fragment of brevican in temporal lobe and hippocampus. This fragment consisted, at least in part, of the ADAMTS-cleaved epitope G1-QEAVESE. The kainate-induced elevation in this ADAMTS-cleaved fragment was localized to amygdaloid and thalamic nuclei, hippocampus, caudate–putamen, cingulate cortex, and the outer molecular layer of the dentate gyrus where it was accompanied by a robust elevation in ADAMTS1 and 4 mRNA and a 28% decline in synaptic density 5 days after kainate. Thus, complexes of extracellular matrix proteins that exist in perineuronal nets and in the neuropil are cleaved by specific matrix-degrading proteases at early time points during excitotoxic neurodegeneration. The observed ADAMTS-induced cleavage of brevican in the dentate outer molecular layer is closely associated with diminished synaptic density, and may, therefore, contribute to synaptic loss and/or reorganization in this region.

Synaptogenesis in the prefrontal cortex of rhesus monkeys.

Since the turn of the century, the prefrontal association areas of the cerebral cortex have been thought to be among the last regions of the cortical mantle to develop. We have examined the course of synaptogenesis in the macaque prefrontal cortex by quantitative electron microscopic analysis in 25 rhesus monkeys ranging in age from embryonic day 47 (E47) to 20 years of age. A series of overlapping electron micrographs spanning the whole cortical thickness in each animal provided data on the number, the proportion, and the density of synapses per unit area (NA) and per unit volume (NV) of neuropil. The tempo and kinetics of synapse formation in prefrontal cortex closely resemble those described for sensory and motor areas, particularly during the stages of synapse acquisition and overproduction (Rakic et al., 1986). In young embryos, we describe a precortical phase (E47-E78), when synapses are found only above and below, but not within, the cortical plate. Following that, there is an early cortical phase, from E78 to E104, during which synapses accumulate within the cortical plate, initially exclusively on dendritic shafts. The next rapid phase of synaptogenesis begins at 2 months before birth and ends approximately at 2 months after birth, culminating with a mean density of 750 million synapses per cubic micrometer. This accumulation is largely accounted for by a selective increase in axospine synapses in the supragranular layers. The period of explosive synaptic density is followed by a protracted plateau stage that lasts from 2 months to 3 years of age when synaptic density remains relatively constant. The final period of decline, from 3 years through over 20 years of age, is marked by a slight but statistically significant decline in synaptic density. Concurrent recruitment of synapses with that of sensory and motor areas supports the concept that the initial establishment of cortical circuitry is governed by general mechanisms common to all areas, independent of their specific functional domain. The finding that synaptic density is relatively stable from early adolescence through puberty (the plateau period) is indicative of the importance, in primates, of a consistent and high synaptic density during the formative years when learning experiences are most intense.

Quantitation of synaptic density in the septal nuclei of young and aged Fischer 344 rats

Synaptic density in the medial and lateral septal nuclei was examined in 3 and 24–28 months of age Fischer 344 rats. The lateral nucleus had a higher synaptic density than the medial region in both age groups. There were no statistically significant differences in synapse density in either region as a function of age, but the data suggested a subpopulation of aged animals which did show an age-related decline in synaptic density in the lateral, but not medial area of the septum. These data indicate that sample size may be an important variable in assessing possible age-related differences in synaptic density, since a broad range of values, some significantly below the range of young animals, exists in the aged brain.

Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life

The density and proportion of synaptic contacts in the primate motor cortex (Brodmann area 4) were determined in 21 rhesus monkeys ranging in age from embryonic day 41 (E41) to 20 years. Two to 4 vertical electron microscopic probes, each consisting of 150–250 overlapping micrographs traversing the thickness of the cortex, were prepared for each specimen. Synapses were categorized according to their morphology (symmetrical or asymmetrical), cellular location (on spines, shafts or soma), number, and ratio of laminar distribution. The density of synapses was expressed per unit area and volume of neuropil (excluding neuronal and glia cell bodies, myelin sheath, blood vessels and extracellular space). The first synapse in the area of the emerging motor cortex were observed at E53 in the marginal zone (prospective layer I) and in the transient subplate zone situated beneath the developing cortical plate. Around midgestation (E89) synapses were observed over the entire width of the cortical plate, and their density was about 5/100 μm 3 of neuropil. During the last two months of gestation synaptic density increased 8-fold across all layers to reach about 40/100 μm 3 at the time of birth (E165). Synaptic production continued postnatally and by the end of the second postnatal month attained a level of 60/100 μm 3 neuropil which is two times higher than in the adults. This level decreased at a slow rate until sexual maturity (3 years of age) and then more rapidly to the adult level which is characterized by relative stability of about 30/100 μm 3. The decline in synaptic density after the peak in infancy occurs predominantly at the expense of asymmetric synapses situated on dendritic spines; the population of symmetric synapses on dendritic shafts remains relatively constant. The development of synaptic connections in the motor cortex of non-human primates involves initial overproduction followed by selective elimination and structural alterations.

Neocortical synaptogenesis, aging, and behavior: Lifespan development in the motor-sensory system of the rat

Little evidence presently exists on the development and aging of synaptic contacts and their relationship to behavior, particularly in nonvisual brain areas. To investigate this interrelationship, rats at a series of developmental ages [postnatal day 1 (P1) to P90] were initially examined on a battery of motor tasks. The battery, ranging from simple reflexive tests to tests of complex locomotor capacities, consisted of tactile-induced forelimb placing, chin-induced placing, body righting, climbing an inclined plane, traversing a narrow beam, and keeping up with a revolving wheel. Following completion of the behavioral testing, the animals, together with an additional group of aged (28- to 29-month-old) rats, were killed and their motor-sensory cortex was removed, stained with osmium tetroxide or ethanol phosphotungstic acid (EPTA), and examined under electron microscopy for density of synaptic contacts. Simple motor abilities such as tactile-induced placing was present by the end of the first postnatal week, with locomotor performance reaching a mature level by the end of the third postnatal week, and intermediate task abilities maturing within this range. Paralleling the development of complex locomotor skills was a sharp increase in synaptic density in the molecular layer of the motor-sensory cortex, commencing in the second postnatal week and peaking at P30. After P30 there was a sharp decline in synaptic density as well as a decline in performance on some motor tasks, although these two functions seemed to be occurring independently. There was a continued, but less dramatic synaptic loss evident in the aged rats.

Age-related changes in the subiculum of Macaca mulatta: Synaptic density

Dendritic spines and synapses were quantitated in the subiculum of 12 Macaca mulatta from 7 to 29 years of age. Dendritic spines were analyzed in six dendritic foci of pyramidal neurons impregnated by the Golgi-Cox method. The dendritic foci examined were the apical shaft, apical oblique, apical tuft, apical terminal, basal terminal, and basal dendrites. Electron microscopic observations were made on synapses stained with ethanolic phosphotungstic acid. There was no difference in spine density between a group of young (7 to 12 years of age) and middle-aged (18 to 21 years) animals. The mean spine density was 1.09/μm for the young and 1.15/μm for the middle-aged animals. In contrast, the spine density of the old animals was 0.87/μm, which was significantly lower than the spine density found in the young and middle-aged animals. A loss of dendritic spines in the old animals occurred equally in all six dendritic foci. A decline in synaptic density in the aged animals were further evidenced by an ultrastructural analysis. The synaptic density of the old animals was 8.3 × 10 8/mm 3, significantly lower than 9.5 × 10 8/mm 3 and 10.2 × 10 8/mm 3 found in the young and middle-aged animals, respectively. This study on synaptic density demonstrated the decline in synaptic number as a function of age in M. mulatta.

Age-related changes in prefrontal cortex of Macaca mulatta: Synaptic density

Age-related changes in synaptic density were quantitated in the prefrontal cortex of nine Macaca mulatta from 7 to 28 years of age. Ultrastructural and light microscopic observations were made on synapses stained with ethanolic phosphotungstic acid and dendritic spines impregnated by the Golgi method, respectively. Ultrastructural analysis revealed the mean synaptic density of 8.77 × 10 8/mm 3 in the cortex of six adult M. mulatta between 7 and 20 years of age. In contrast, the synaptic density of the three oldest M. mulatta, between 27 and 28 years of age, was 6.93 × 10 8/mm 3. Age-related decline in synaptic density was also evidenced by light microscopic quantitation of dendritic spines. The spine density of the three oldest M. mulatta was 0.72/μm, significantly lower than 0.98/μm found in the six young-adult M. mulatta. The data obtained in this study also suggest that the loss of synapses of the cortical neuron is not confined to any one particular segment of the dendrites.

Synaptic density in human frontal cortex — Developmental changes and effects of aging

Density of synaptic profiles in layer 3 of middle frontal gyrus was quantitated in 21 normal human brains ranging from newborn to age 90 years. Synaptic profiles could be reliably demonstrated by the phosphotungstic acid method (Bloom and Aghajanian 3) in tissue fixed up to 36 h postmortem. Synaptic density was constant throughout adult life (ages 16–72 years) with a mean of 11.05 × 10 8synapses/cu.mm ± 0.41 S.E.M.. There was a slight decline in synaptic density in brains of the aged (ages 74–90 years) with a mean of 9.56 × 10 8synapses/cu.mm ± 0.28S.E.M. in 4 samples ( P < 0.05). Synaptic density in neonatal brains was already high—in the range seen in adults. However, synaptic morphology differed; immature profiles had an irregular presynaptic dense band instead of the separate presynaptic projections seen in mature synapses. Synaptic density increased during infancy, reaching a maximum at age 1–2 years which was about 50% above the adult mean. The decline in synaptic density observed between ages 2–16 years was accompanied by a slight decrease in neuronal density. Human cerebral cortex is one of a number of neuronal systems in which loss of neurons and synapses appears to occur as a late developmental event.