Synaptic Structures Research Articles

Chronic social defeat stress induces sustained synaptic structural changes in the prefrontal cortex and amygdala

Previous studies show that chronic stress induces synaptic structural alterations in brain regions involved in emotional processing such as the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Yet, these studies are based mainly in animal exposure to unpredictable stressors or to restraint stress. On the other hand, studies using the chronic social defeat stress (CSDS), a relevant model of depression based on social conflict, are lacking. Here we aim to study the acute (24 h after CSDS) and long-term (one month after CSDS) effects of CSDS on dendritic and synaptic structures in the PFC and BLA of C57BL/6 mice. Specifically, BLA and PFC dendritic spine densities as well as BLA arborisation were analysed. Subsequently, we investigate in these regions the synaptic response to a friendly (interaction with a same strain mouse) or a fearful (interaction with a dominant strain mouse) social stimulus.Spine densities of the apical dendrites from the PFC pyramidal neurons were decreased by CSDS in the long-term (one month after CSDS). In addition, CSDS increased BLA stellate neurons spine density in the short-term (24 h after CSDS) and dendritic arborisation in the long-term. Moreover, long-term CSDS mice exposed to a fearful stimulus experienced a marked social avoidance and showed a significant increase in the expression of the immature form of the brain derived neurotrophic factor (proBDNF) in the amygdala.Taken together these results suggest the existence of persistent neuronal adaptations in the PFC and BLA in socially defeated mice. Specifically, spine density retraction in the PFC and increased BLA dendritic arborisation could represent an adaptive structural change allowing rapid expression of synaptic markers in response to fearful experiences.

Activation of Rod Input in a Model of Retinal Degeneration Reverses Retinal Remodeling and Induces Formation of Functional Synapses and Recovery of Visual Signaling in the Adult Retina.

A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells disappear and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and are thought to occur in response to deafferentation. How the remodeled retinal circuit affects visual processing following rod rescue is not known. To address this question, we generated male and female transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channels exhibit a resting membrane potential that was ~10 mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.SIGNIFICANCE STATEMENT Current strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neurons function within a complex neural circuitry, which also becomes degraded during disease. It is not known whether rescued neurons and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward dendrites of rod bipolar cells re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.

Subsynaptic Domains in Super-Resolution Microscopy: The Treachery of Images.

The application of super-resolution optical microscopy to investigating synaptic structures has revealed a highly heterogeneous and variable intra-synaptic organization. Dense subsynaptic protein assemblies named subsynaptic domains or SSDs have been proposed as structural units that regulate the efficacy of neuronal transmission. However, an in-depth characterization of SSDs has been hampered by technical limitations of super-resolution microscopy of synapses, namely the stochasticity of the signals during the imaging procedures and the variability of the synaptic structures. Here, we synthetize the available evidence for the existence of SSDs at central synapses, as well as the possible functional relevance of SSDs. In particular, we discuss the possible regulation of co-transmission at mixed inhibitory synapses as a consequence of the subsynaptic distribution of glycine receptors (GlyRs) and GABAA receptors (GABAARs).LAY ABSTRACTSuper-resolution imaging strategies bypass the resolution limit of conventional optical microscopy and have given new insights into the distribution of proteins at synapses in the central nervous system. Neurotransmitter receptors and scaffold proteins appear to occupy specialized locations within synapses that we refer to as subsynaptic domains or SSDs. Interestingly, these SSDs are highly dynamic and their formation seems to be related to the remodeling of synapses during synaptic plasticity. It was also shown that SSDs of pre-and post-synaptic proteins are aligned in so-called nanocolumns, highlighting the role of SSDs in the regulation of synaptic transmission. Despite recent advances, however, the detection of SSDs with super-resolution microscopy remains difficult due to the inherent technical limitations of these approaches that are discussed in this review article.

Proteomic Analysis of Rat Cerebral Cortex in the Subacute to Long-Term Phases of Focal Cerebral Ischemia-Reperfusion Injury.

Stroke is a leading cause of mortality and disability, and ischemic stroke accounts for more than 80% of the disease occurrence. Timely reperfusion is essential in the treatment of ischemic stroke, but it is known to cause ischemia-reperfusion (I/R) injury and the relevant studies have mostly focused on the acute phase. Here we reported on a global proteomic analysis to investigate the development of cerebral I/R injury in the subacute and long-term phases. A rat model was used, with 2 h-middle cerebral artery occlusion (MCAO) followed with 1, 7, and 14 days of reperfusion. The proteins of cerebral cortex were analyzed by SDS-PAGE, whole-gel slicing, and quantitative LC-MS/MS. Totally 5621 proteins were identified, among which 568, 755, and 492 proteins were detected to have significant dys-regulation in the model groups with 1, 7, and 14 days of reperfusion, respectively, when compared with the corresponding sham groups (n = 4, fold change ≥1.5 or ≤0.67 and p ≤ 0.05). Bioinformatic analysis on the functions and reperfusion time-dependent dys-regulation profiles of the proteins exhibited changes of structures and biological processes in cytoskeleton, synaptic plasticity, energy metabolism, inflammation, and lysosome from subacute to long-term phases of cerebral I/R injury. Disruption of cytoskeleton and synaptic structures, impairment of energy metabolism processes, and acute inflammation responses were the most significant features in the subacute phase. With the elongation of reperfusion time to the long-term phase, a tendency of recovery was detected on cytoskeleton, while inflammation pathways different from the subacute phase were activated. Also, lysosomal structures and functions might be restored. This is the first work reporting the proteome changes that occurred at different time points from the subacute to long-term phases of cerebral I/R injury and we expect it would provide useful information to improve the understanding of the mechanisms involved in the development of cerebral I/R injury and suggest candidates for treatment.

DiI-mediated analysis of presynaptic and postsynaptic structures in human postmortem brain tissue.

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.

Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function.

ABSTRACTAltered cortical excitability and synapse dysfunction are early pathogenic events in amyotrophic lateral sclerosis (ALS) patients and animal models. Recent studies propose an important role for TAR DNA-binding protein 43 (TDP-43), the mislocalization and aggregation of which are key pathological features of ALS. However, the relationship between ALS-linked TDP-43 mutations, excitability and synaptic function is not fully understood. Here, we investigate the role of ALS-linked mutant TDP-43 in synapse formation by examining the morphological, immunocytochemical and excitability profile of transgenic mouse primary cortical pyramidal neurons that over-express human TDP-43A315T. In TDP-43A315T cortical neurons, dendritic spine density was significantly reduced compared to wild-type controls. TDP-43A315T over-expression increased the total levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropinionic acid (AMPA) glutamate receptor subunit GluR1, yet the localization of GluR1 to the dendritic spine was reduced. These postsynaptic changes were coupled with a decrease in the amount of the presynaptic marker synaptophysin that colocalized with dendritic spines. Interestingly, action potential generation was reduced in TDP-43A315T pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43A315T on the formation of synaptic structures and the recruitment of GluR1 to the synaptic membrane. This pathogenic effect may be mediated by cytoplasmic mislocalization of TDP-43A315T. Loss of synaptic GluR1, and reduced excitability within pyramidal neurons, implicates hypoexcitability and attenuated synaptic function in the pathogenic decline of neuronal function in TDP-43-associated ALS. Further studies into the mechanisms underlying AMPA receptor-mediated excitability changes within the ALS cortical circuitry may yield novel therapeutic targets for treatment of this devastating disease.

Dexamethasone ameliorates the damage of hippocampal filamentous actin cytoskeleton but is not sufficient to cease epileptogenesis in pilocarpine induced epileptic mice

Rogressive deconstruction of filament actin (F-actin) in hippocampal neurons in the epileptic brain have been associated with epileptogenesis. Previous clinical studies suggest that glucocorticoids treatment plays beneficial roles in refractory epilepsy. Glucocorticoids treatment affects dendritic spine morphology by regulating local glucocorticoid receptors and F-actin cytoskeleton dynamics. However, how glucocorticoids regulate epileptogenesis by controlling F-actin cytoskeleton is not clear yet. Here we study the function of glucocorticoids in epileptogenesis by examining F-actin abundance, hippocampal neuron number, and synaptic markers in pilocarpine-induced epileptic mice in the presence or absence of dexamethasone (DEX) treatment. We found that spontaneous seizure duration was significantly reduced; F-actin damage in hippocampal subfields was remarkably attenuated; loss of pyramidal cells was dramatically decreased; more intact synaptic structures indicated by pre- and postsynaptic markers were preserved in multiple hippocampal regions after DEX treatment. However, the number of ZNT3 positive particles in the molecular layer in the hippocampus of pilocarpine epileptic mice was not altered after DEX treatment. Although not sufficient to cease epileptogenesis, our results suggest that dexamethasone treatment ameliorates the damage of epileptic brain by stabilizing F-actin cytoskeleton in the pilocarpine epileptic mice.

NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model.

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.

The role of astrocytes on the effects of exercise on episodic memory function.

This review discusses the potential role that glial cells may play in influencing the relationship between exercise and episodic memory function. A narrative review methodology is employed. Herein, the different types of glial cells, their implications in subserving episodic memory function, and how exercise can modulate glial cell activity, particularly astrocyte functionality, are discussed. Although additional experimental work is needed, astrocytes appear to play an important role in the exercise-memory interaction. Exercise may increase astrocytic size, attenuate astrogliodegeneration, improve astrocytic aquaporin-4 expression, and increase astrocytic transporter levels. These effects, in turn, may help to increase the number of synapses that neurons form, increase the number of synaptic structures, and increase presynaptic function and postsynaptic receptor localization. Ultimately, these effects may help influence long-term potentiation and episodic memory function.

Biomechanics of Blast TBI With Time-Resolved Consecutive Primary, Secondary, and Tertiary Loads.

Blast-induced traumatic brain injury (bTBI) has become a signature casualty of recent military operations. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics may help in better understanding of injury mechanisms and in the development of improved neuroprotective strategies. Until present, bTBI has been analyzed as a single event of a blast pressure wave propagating through the brain. In many bTBI events, the loads on the body and the head are spatially and temporarily distributed, involving the primary intracranial pressure wave, followed by the head rotation and then by head impact on the ground. In such cases, the brain microstructures may experience time/space distributed (consecutive) damage and recovery events. The paper presents a novel multiscale simulation framework that couples the body/brain scale biomechanics with micro-scale mechanobiology to study the effects of micro-damage to neuro-axonal structures. Our results show that the micro-mechanical responses of neuro-axonal structures occur sequentially in time with "damage" and "relaxation" periods in different parts of the brain. A new integrated computational framework is described coupling the brain-scale biomechanics with micro-mechanical damage to axonal and synaptic structures.

Dysfunctional Mitochondrial Bioenergetics and Synaptic Degeneration in Alzheimer Disease.

Synapses are sites of high energy demand which are dependent on high levels of mitochondrial derived adenosine triphosphate. Mitochondria within synaptic structures are key for maintenance of functional neurotransmission and this critical biological process is modulated by energy metabolism, mitochondrial distribution, mitochondrial trafficking, and cellular synaptic calcium flux. Synapse loss is presumed to be an early yet progressive pathological event in Alzheimer disease (AD), resulting in impaired cognitive function and memory loss which is particularly prevalent at later stages of disease. Supporting evidence from AD patients and animal models suggests that pathological mitochondrial dynamics indeed occurs early and is highly associated with synaptic lesions and degeneration in AD neurons. This review comprehensively highlights recent findings that describe how synaptic mitochondria pathology involves dysfunctional trafficking of this organelle, to maladaptive epigenetic contributions affecting mitochondrial function in AD. We further discuss how these negative, dynamic alterations impact synaptic function associated with AD. Finally, this review explores how antioxidant therapeutic approaches targeting mitochondria in AD can further clinical research and basic science investigations to advance our in-depth understanding of the pathogenesis of AD.

Inhibition of Bruton\u2019s Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer\u2019s Disease

Bruton’s tyrosine kinase (BTK), a critical component of B cell receptor signaling, has recently been implicated in regulation of the peripheral innate immune response. However, the role of BTK in microglia, the resident innate immune cells of the central nervous system, and its involvement in the pathobiology of neurodegenerative disease has not been explored. Here we found that BTK is a key regulator of microglial phagocytosis. Using potent BTK inhibitors and small interfering RNA (siRNA) against BTK, we observed that blockade of BTK activity decreased activation of phospholipase gamma 2, a recently identified genetic risk factor in Alzheimer’s disease (AD), and reduced phagocytosis in rodent microglia and human monocyte-derived macrophages. Inhibition of BTK signaling also decreased microglial uptake of synaptosomes but did not have major impacts on other key microglial functions such as migration and cytokine release. Similarly, blocking BTK function ex vivo in acute brain slices reduced microglial phagocytosis and maintained numbers of resting microglia. In brain tissues from the 5xFAD mouse model of AD, levels of microglial BTK were elevated while in two gene expression datasets of post-mortem AD patient brain tissues, upregulation of BTK transcript was observed. Our study provides novel insights into the role of BTK in regulating microglial phagocytosis and uptake of synaptic structures and suggests that inhibiting microglial BTK may improve cognition in AD by preventing microglial activation and synaptic loss.Graphical Microglial-mediated synapse loss has been implicated in AD pathogenesis. Inhibition of BTK decreases activation of PLCγ2, a genetic risk factor in AD, and reduces microglial phagocytosis and uptake of synaptic structures. As such BTK inhibition may represent a therapeutic route to prevent microglial activation and synapse loss in AD

Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.

Organotypic and primary neural cultures as models to assess effects of different gold nanostructures on glia and neurons

Gold nanoparticles (AuNP) have unique physicochemical properties and have been used as delivery vehicles, contrast agents, and therapeutic compounds. Although the effects of AuNPs on peripheral tissues and immortalized cell lines have been extensively characterized, their effects on the central nervous system (CNS) are predominantly unknown. The main objective of the current study was to evaluate how AuNPs of varying sizes (1–100 nm), shapes (clusters, spheres, rods, flowers), and surfaces impact synaptic structures in the hippocampus, a brain structure often affected in neurodegeneration. Using a combination of organotypic hippocampal, as well as, primary neuronal, glial, and astrocytic cultures, we examined AuNPs impact on hippocampal dendritic spine density, internalization in various neural cells, and lysosomal status in astrocytes. Considering that neurons interact with astrocytes, and that lysosomes play a role in dendritic spine status, transcription factor TFEB and abundance of lysosomal marker, LAMP1 were evaluated. Both biomarkers were significantly increased in astrocytes exposed to AuNPs, suggesting that AuNPs not only enter lysosomes, but also increase lysosome biogenesis. Results from our studies show that AuNPs with poly(ethylene glycol) (AuNPs-PEG) or glutathione (AuNP-GSH) surfaces do not substantially decrease hippocampal dendritic spine density. Conversely, AuNPs coated with the detergent, CTAB, significantly decreased total spine density. Interestingly small gold nanoclusters (Au15(SG)13) with GSH reduced spine density, whereas larger gold nanoclusters (Au25(SG)18) with the same ligand did not. Thus, assessment of dendritic morphology, spine densities can reveal subtler changes of neural cells than cell death when exposed to nanoparticles, including AuNPs.

Impairment of Dendrodendritic Inhibition in the Olfactory Bulb of APP/PS1 Mice.

Olfactory dysfunction is an early event in Alzheimer’s disease (AD). However, the mechanism underlying the AD-related changes in the olfactory bulb (OB) remains unknown. Granule cells (GCs) in the OB regulate the activity of mitral cells (MCs) through reciprocal dendrodendritic synapses, which is crucial for olfactory signal processing and odor discrimination. Nevertheless, the relationships between the morphological and functional changes of dendrodendritic synapses, particularly the local field potentials (LFPs) as a consequence of olfactory disorders in patients with AD have not been investigated. Here, we studied the morphological and functional changes induced by dendrodendritic inhibition in GCs onto MCs in the OB of amyloid precursor protein (APP)/PS1 mice and age-matched control mice during aging, particular, we focused on the effects of olfactory disorder in the dendrodendritic synaptic structures and the LFPs. We found that olfactory disorder was associated with increased amyloid-β (Aβ) deposits in the OB of APP/PS1 mice, and those mice also exhibited abnormal changes in the morphology of GCs and MCs, a decreased density of GC dendritic spines and impairments in the synaptic interface of dendrodendritic synapses between GCs and MCs. In addition, the aberrant enhancements in the γ oscillations and firing rates of MCs in the OB of APP/PS1 mice were recorded by multi-electrode arrays (MEAs). The local application of a GABAAR agonist nearly abolished the aberrant increase in γ oscillations in the external plexiform layer (EPL) at advanced stages of AD, whereas a GABAAR antagonist aggravated the γ oscillations. Based on our findings, we concluded that the altered morphologies of the synaptic structures of GCs, the dysfunction of reciprocal dendrodendritic synapses between MCs and GCs, and the abnormal γ oscillations in the EPL might contribute to olfactory dysfunction in AD.

MiR-22 exerts anti-alzheimic effects via the regulation of apoptosis of hippocampal neurons

To investigate the expression of miR-22 in the hippocampus of amyloid β (1-42)-induced alzheimic rats, and to assess the underlying mechanism. A total of 60 male Sprague Dawley rats weighing between 274.65 and 293.97 g (mean weight = 284.31 ± 9.66 g) and aged 12 to 14 weeks were randomly assigned to three groups: control group (n = 20), Alzheimer's disease group (AD group; n = 20) and AD + miR-22 mimic group (ADMM group; n = 22). Rat AD model was established by injecting a solution of Aβ1-42 into the hippocampal CA1 regions. After 24 h, rats in the ADMM group also received intraventricular injection of miR-22 mimic continuously for 28 days. The escape latency of rats, neuronal damage in the hippocampus, synaptic structure, brain-derived neurotrophic factor (BDNF), and the expressions of apoptosis-related proteins were assessed or determined, as appropriate. The expression of miR-22 in hippocampus of the AD group was significantly lower than that in the control group (p < 0.05). However, after 28 days of intraventricular injection of miR-22 mimic into AD rats, the expression was significantly increased, relative to control (p < 0.05). The escape latency of AD rats was significantly prolonged, and the number of platform sites significantly reduced when compared to the control group (p < 0.05). However, the escape latency was significantly shortened and the number of platform sites significantly increased in the ADMM group, relative to the control and AD groups. Results of transmission electron microscopy showed that the expression of miR-22 significantly reversed the degradation of synaptic structures in the hippocampus of AD rats as evidenced by recovery of abnormal synaptic cleft width and the length of synaptic active zones (p < 0.05). Results of Nissl staining revealed significant proliferation of gliacyte and loss of Nissl bodies. After miR-22 injection, the number of gliacytes in the hippocampus of AD rats was significantly reduced, while the number of Nissl bodies was significantly increased (p < 0.05). The expressions of BDNF in CA1 and CA2/3 regions of AD rats were significantly lower than those in the control group, and BDNF in the hippocampus of AD rats was significantly increased after 28 days of continuous injection of miR-22 (p < 0.05). The positive expression of Tunnel in the ADMM group (22.67 ± 2.96 %) was significantly higher than that in the AD group (4.49 ± 1.23 %), but significantly lower than that of control (39.51 ± 3.66 %) (p < 0.05). After 28 days of intraventricular injection of miR-22 mimic into AD rats, the expression of Bax protein was significantly down-regulated, while bcl-2 protein was significantly up-regulated (p < 0.05). The expression of miR-22 in the hippocampus of patients with AD inhibits neuronal apoptosis, thereby improving learning and memory dysfunction.

Oxytocin inhibits methamphetamine-associated learning and memory alterations by regulating DNA methylation at the Synaptophysin promoter.

Methamphetamine (METH) causes memory changes, but the underlying mechanisms are poorly understood. Epigenetic mechanisms, including DNA methylation, can potentially cause synaptic changes in the brain. Oxytocin (OT) plays a central role in learning and memory, but little is known of the impact of OT on METH-associated memory changes. Here, we explored the role of OT in METH-induced epigenetic alterations that underlie spatial and cognitive memory changes. METH (2.0mg/kg, i.p.) was administered to male C57BL/6 mice once every other day for 8days. OT (2.5μg, i.c.v.) or aCSF was given prior to METH. Spatial and cognitive memory were assessed. In Hip and PFC, synaptic structures and proteins were examined, levels of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MECP2) were determined, and the DNA methylation status at the Synaptophysin (Syn) promoter was assessed. METH enhanced spatial memory, decreased synapse length, downregulated DNMT1, DNMT3A, DNMT3B, and MECP2, and induced DNA hypomethylation at the Syn promoter in Hip. In contrast, METH reduced cognitive memory, increased synapse thickness, upregulated DNMT1, DNMT3A, and MECP2, and induced DNA hypermethylation at the Syn promoter in PFC. OT pretreatment specifically ameliorated METH-induced learning and memory alterations, normalized synapse structures, and regulated DNMTs and MECP2 to reverse the DNA methylation status changes at the Syn promoter in Hip and PFC. DNA methylation is an important gene regulatory mechanism underlying METH-induced learning and memory alterations. OT can potentially be used to specifically manipulate METH-related memory changes.

Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience.

Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.

The Emerging Role of Mechanics in Synapse Formation and Plasticity.

The regulation of synaptic strength forms the basis of learning and memory, and is a key factor in understanding neuropathological processes that lead to cognitive decline and dementia. While the mechanical aspects of neuronal development, particularly during axon growth and guidance, have been extensively studied, relatively little is known about the mechanical aspects of synapse formation and plasticity. It is established that a filamentous actin network with complex spatiotemporal behavior controls the dendritic spine shape and size, which is thought to be crucial for activity-dependent synapse plasticity. Accordingly, a number of actin binding proteins have been identified as regulators of synapse plasticity. On the other hand, a number of cell adhesion molecules (CAMs) are found in synapses, some of which form transsynaptic bonds to align the presynaptic active zone (PAZ) with the postsynaptic density (PSD). Considering that these CAMs are key components of cellular mechanotransduction, two critical questions emerge: (i) are synapses mechanically regulated? and (ii) does disrupting the transsynaptic force balance lead to (or exacerbate) synaptic failure? In this mini review article, I will highlight the mechanical aspects of synaptic structures—focusing mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation of synapses and its relevance to neurodegenerative diseases.

Fine structure of the silk gland in the mite Ornithocheyletia sp. (Prostigmata, Cheyletidae).

Silk spinning is widely-spread in trombidiform mites, yet scarse information is available on the morphology of their silk glands. Thus this study describes the fine structure of the prosomal silk glands in a small parasitic mite, Ornithocheyletia sp. (Cheyletidae). These are paired acinous glands incorporated into the podocephalic system, as typical of the order. Combined secretion of the coxal and silk glands is released at the tip of the gnathosoma. Data obtained show Ornithocheyletia silk gland belonging to the class 3 arthropod exocrine gland. Each gland is composed of seven pyramidal secretory cells and one ring-folded intercalary cell, rich in microtubules. The fine structure of the secretory cells points to intensive protein synthesis resulted in the presence of abundant uniform secretory granules. Fibrous content of the granules is always subdivided into several zones of two electron densities. The granules periodically discharge into the acinar cavity by means of exocytosis. The intercalary cell extends from the base of the excretory duct and contributes the wall of the acinar cavity encircling the apical margins of the secretory cells. The distal apical surface of the intercalary cell is covered with a thin cuticle resembling that of the corresponding cells in some acarine and myriapod glands. Axon endings form regular synaptic structures on the body of the intercalary cell implying nerve regulation of the gland activity.