Density Of Synapses Research Articles

Developing forebrain synapses are uniquely vulnerable to sleep loss

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long-lasting changes in adult behavior. Divergent plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21 to P28), adolescent (P42 to P49), and adult (P70 to P100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition task. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of perineuronal nets. Our analysis further reveals the developing synapse as a putative node of convergence between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing insights for ASD susceptibility.

Glutamate signaling and neuroligin/neurexin adhesion play opposing roles that are mediated by major histocompatibility complex I molecules in cortical synapse formation.

Although neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation (Verhage et al., 2000; Sando et al., 2017; Sigler et al., 2017; Held et al., 2020), yet glutamate clearly regulates glutamate receptor trafficking (Roche et al., 2001; Nong et al., 2004) and induces spine formation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999; Toni et al., 1999; Kwon and Sabatini, 2011; Oh et al., 2016). Using rat and murine culture systems to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing N-methyl-D-aspartate receptor (NMDAR) transport and surface expression as well as co-transport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels in both sexes. Thus, like acetylcholine at the neuromuscular junction (NMJ), glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.Significance Statement The role for neurotransmitter release in synaptogenesis in the central nervous system (CNS) remains unclear. Here, we reconcile conflicting results in the field by showing that glutamate plays an important role in synapse formation by acting as a dispersal signal for NMDARs that is counteracted by trans-synaptic adhesion in intact tissue, similar to the role for neurotransmitter at the NMJ. We also describe a novel form of homeostatic plasticity in young neurons that allows them to respond to changes in activity through surprisingly rapid changes in synapse density. Finally, we show that this plasticity is modulated by immune proteins-MHCI molecules-through negative regulation of NL1 levels, connecting two important synaptic signaling pathways for the first time.

Regulation of synapse density by Pumilio RNA-binding proteins

Regulation of synapse density by Pumilio RNA-binding proteins

Postnatal Enrichment Corrects Deficits in Perineuronal Net Formation and Reversal Learning in Adult Mice Exposed to Early Adversity.

Childhood neglect is associated with cortical thinning, hyperactivity, and deficits in cognitive flexibility that are difficult to reverse later in life. Despite being the most prevalent form of early adversity, little is currently understood about the mechanisms responsible for these neurodevelopmental abnormalities, and no animal models have yet replicated key structural and behavioral features of childhood neglect/deprivation. To address these gaps, we have recently demonstrated that mice exposed to impoverished conditions, specifically limited bedding (LB), exhibit behavioral and structural changes that resemble those observed in adolescents who have experienced severe neglect. Here, we show that LB leads to long-term deficits in reversal learning, which can be fully reversed by briefly exposing LB pups to enrichment (toys) in their home cage from postnatal days 14 to 25. Reversal learning failed to induce normal c-fos activation in the orbitofrontal cortex (OFC) of LB mice, a deficit that was normalized by early enrichment. Additionally, LB decreased the density of parvalbumin-positive cells surrounded by perineuronal nets (PV+PNN+) and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC, deficits that were also reversed by enrichment. Degradation of PNN in the OFC of adult mice impaired reversal learning, reduced c-fos activation, and increased the ratio of glutamatergic to inhibitory synapse densities in the OFC to levels comparable to those observed in LB mice. Collectively, our findings suggest that postnatal deprivation and enrichment impact the formation of PV+PNN+ cells in the OFC, a developmental process that is essential for cognitive flexibility in adulthood.

Human Pluripotent Stem Cell-Derived Astrocyte Functionality Compares Favorably with Primary Rat Astrocytes.

Astrocytes are essential for the formation and maintenance of neural networks. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Despite recent advances in human pluripotent stem cell (hPSC) techniques, primary rodent astrocytes remain the gold standard in coculture with human neurons. We demonstrate that a combination of leukemia inhibitory factor (LIF) and bone morphogenetic protein-4 (BMP4) directs hPSC-derived neural precursor cells to a highly pure population of astroglia in 28 d. Using single-cell RNA sequencing, we confirm the astroglial identity of these cells and highlight profound transcriptional adaptations in cocultured hPSC-derived astrocytes and neurons, consistent with their further maturation. In coculture with human neurons, multielectrode array recordings revealed robust network activity of human neurons in a coculture with hPSC-derived or rat astrocytes [3.63 ± 0.44 min-1 (hPSC-derived), 2.86 ± 0.64 min-1 (rat); p = 0.19]. In comparison, we found increased spike frequency within network bursts of human neurons cocultured with hPSC-derived astrocytes [56.31 ± 8.56 Hz (hPSC-derived), 24.77 ± 4.04 Hz (rat); p < 0.01], and whole-cell patch-clamp recordings revealed an increase of postsynaptic currents [2.76 ± 0.39 Hz (hPSC-derived), 1.07 ± 0.14 Hz (rat); p < 0.001], consistent with a corresponding increase in synapse density [14.90 ± 1.27/100 μm2 (hPSC-derived), 8.39 ± 0.63/100 μm2 (rat); p < 0.001]. Taken together, we show that hPSC-derived astrocytes compare favorably with rat astrocytes in supporting human neural network activity and maturation, providing a fully human platform for investigating astrocyte function and neuronal-glial interactions.

Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function.

The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.

Repetitive mild closed-head injury induced synapse loss and increased local BOLD-fMRI signal homogeneity.

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries, requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild closed-head injury (rmTBI) and chronic variable stress (CVS) mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [18F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an increase in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

Sleep maintains excitatory synapse diversity in the cortex and hippocampus

Insufficient sleep is a global problem with serious consequences for cognition and mental health.1 Synapses play a central role in many aspects of cognition, including the crucial function of memory consolidation during sleep.2 Interference with the normal expression or function of synapse proteins is a cause of cognitive, mood, and other behavioral problems in over 130 brain disorders.3 Sleep deprivation (SD) has also been reported to alter synapse protein composition and synapse number, although with conflicting results.4,5,6,7 In our study, we conducted synaptome mapping of excitatory synapses in 125 regions of the mouse brain and found that sleep deprivation selectively reduces synapse diversity in the cortex and in the CA1 region of the hippocampus. Sleep deprivation targeted specific types and subtypes of excitatory synapses while maintaining total synapse density (synapse number/area). Synapse subtypes with longer protein lifetimes exhibited resilience to sleep deprivation, similar to observations in aging and genetic perturbations. Moreover, the altered synaptome architecture affected the responses to neural oscillations, suggesting that sleep plays a vital role in preserving cognitive function by maintaining the brain's synaptome architecture.

Structural plasticity of pyramidal cell neurons measured after FLASH and conventional dose-rate irradiation.

Evidence shows that ultra-high dose-rate FLASH-radiotherapy (FLASH-RT) protects against normal tissue complications and functional decrements in the irradiated brain. Past work has shown that radiation-induced cognitive impairment, neuroinflammation and reduced structural complexity of granule cell neurons were not observed to the same extent after FLASH-RT (> MGy/s) compared to conventional dose-rate (CONV, 0.1 Gy/s) delivery. To explore the sensitivity of different neuronal populations to cranial irradiation and dose-rate modulation, hippocampal CA1 and medial prefrontal cortex (PFC) pyramidal neurons were analyzed by electron and confocal microscopy. Neuron ultrastructural analyses by electron microscopy after 10 Gy FLASH- or CONV-RT exposures indicated that irradiation had little impact on dendritic complexity and synapse density in the CA1, but did increase length and head diameter of smaller non-perforated synapses. Similarly, irradiation caused no change in PFC prelimbic/infralimbic axospinous synapse density, but reductions in non-perforated synapse diameters. While irradiation resulted in thinner myelin sheaths compared to controls, none of these metrics were dose-rate sensitive. Analysis of fluorescently labeled CA1 neurons revealed no radiation-induced or dose-rate-dependent changes in overall dendritic complexity or spine density, in contrast to our past analysis of granule cell neurons. Super-resolution confocal microscopy following a clinical dosing paradigm (3×10Gy) showed significant reductions in excitatory vesicular glutamate transporter 1 and inhibitory vesicular GABA transporter puncta density within the CA1 that were largely dose-rate independent. Collectively, these data reveal that, compared to granule cell neurons, CA1 and mPFC neurons are more radioresistant irrespective of radiation dose-rate.

Tau-mediated synaptic dysfunction is coupled with HCN channelopathy.

In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to disease-associated abnormalities in multiple neurodegenerative diseases. To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons. Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization-induced membrane voltage "sag" and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents. Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network-wide structural and functional synaptic deficits. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are functionally linked to the development of tauopathy. Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy. Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization-induced membrane voltage "sag" demonstrating a detrimental effect of tau abnormalities on HCN channel function. Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.

An In Vivo High-Resolution Human Brain Atlas of Synaptic Density.

Synapses are fundamental to the function of the central nervous system and are implicated in a number of brain disorders. Despite their pivotal role, a comprehensive imaging resource detailing the distribution of synapses in the human brain has been lacking until now. Here, we employ high-resolution PET neuroimaging in healthy humans (17F/16M) to create a 3D atlas of the synaptic marker Synaptic Vesicle glycoprotein 2A (SV2A). Calibration to absolute density values (pmol/ml) was achieved by leveraging postmortem human brain autoradiography data. The atlas unveils distinctive cortical and subcortical gradients of synapse density that reflect functional topography and hierarchical order from core sensory to higher-order integrative areas-a distribution that diverges from SV2A mRNA patterns. Furthermore, we found a positive association between IQ and SV2A density in several higher-order cortical areas. This new resource will help advance our understanding of brain physiology and the pathogenesis of brain disorders, serving as a pivotal tool for future neuroscience research.

A dendritic substrate for temporal diversity of cortical inhibition.

In the mammalian neocortex, GABAergic interneurons (INs) inhibit cortical networks in profoundly different ways. The extent to which this depends on how different INs process excitatory signals along their dendrites is poorly understood. Here, we reveal that the functional specialization of two major populations of cortical INs is determined by the unique association of different dendritic integration modes with distinct synaptic organization motifs. We found that somatostatin (SST)-INs exhibit NMDAR-dependent dendritic integration and uniform synapse density along the dendritic tree. In contrast, dendrites of parvalbumin (PV)-INs exhibit passive synaptic integration coupled with proximally enriched synaptic distributions. Theoretical analysis shows that these two dendritic configurations result in different strategies to optimize synaptic efficacy in thin dendritic structures. Yet, the two configurations lead to distinct temporal engagement of each IN during network activity. We confirmed these predictions with in vivo recordings of IN activity in the visual cortex of awake mice, revealing a rapid and linear recruitment of PV-INs as opposed to a long-lasting integrative activation of SST-INs. Our work reveals the existence of distinct dendritic strategies that confer distinct temporal representations for the two major classes of neocortical INs and thus dynamics of inhibition.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-β (Aβ) oligomers.

Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AβO. LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AβO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AβO-infused mice. These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density

From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density

Intermittent hypoxia training enhances Aβ endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer’s disease

BackgroundBeta-amyloid (Aβ) deposition in the brain parenchyma is a crucial initiating step in the amyloid cascade hypothesis of Alzheimer’s disease (AD) pathology. Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate Aβ deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric Aβ (oAβ) clearance. Considering that oAβ internalization is the initial stage of oAβ clearance, this study focused on the IHT mechanism involved in upregulating Aβ uptake by DAM.MethodsIHT was administered to 8-month-old APP/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP/PS1 background (MG VPS35 KO: APP/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, Aβ plaque deposition, and Aβ load in the brain. A model of Aβ-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and Aβ internalization were measured using a fluorescence tracing technique.ResultsOur results showed that IHT ameliorated cognitive function and Aβ pathology. In particular, IHT enhanced Aβ endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to Aβ clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on Aβ pathology in MG VPS35 KO: APP/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB).ConclusionIHT enhances Aβ endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oAβ clearance and mitigation of Aβ pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD.Graphical abstract

Neuroprotection of macamide in a mouse model of Alzheimer’s disease involves Nrf2 signaling pathway and gut microbiota

The underlying mechanisms of macamide’s neuroprotective effects in Alzheimer’s disease (AD) were investigated in the paper. Macamides are considered as unique ingredients in maca. Improvement effects and mechanisms of macamide on cognitive impairment have not been revealed. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to acetylcholinesterase (AChE). N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) was selected to study the following experiments because it can stably bind to AChE with a strong binding energy. The animal experiments showed that M 18:2 prevented the scopolamine (SCP)-induced cognitive impairment and neurotransmitter disorders, increased the positive rates of Nrf2 and HO-1 in hippocampal CA1, improved the synaptic plasticity by maintaining synaptic morphology and increasing the synapse density. Moreover, the contents of IL-1β, IL-6, and TNF-α in the hippocampus, serum, and colon were reduced by M 18:2. Furthermore, M 18:2 promoted colonic epithelial integrity and partially restored the composition of the gut microbiota to normal, including decreased genera Clostridiales_unclassified and Lachnospiraceae_unclassified, as well as increased genera Muribaculaceae_unclassified, Muribaculum, Alistipes, and Bacteroides, which may be the possible biomarkers of cognitive aging. In summary, M 18:2 exerted neuroprotective effects on SCP-induced AD mice possibly via activating the Nrf2/HO-1 signaling pathway and modulating the gut microbiota.

Synaptic Profile and Oxidative Stress Associated with Amyloid-β in the Hippocampus

Alzheimer’s Disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. The neuropathology is mainly due to disturbances in neuronal circuits and protein aggregations of phosphorylated tau and Amyloid-β (Aβ). Other factors found in disease progression are oxidative stress, microglial activation, and decreased synaptic transmission. However, it is unknown whether these changes occur only in close association with Aβ plaques, or rather have broad occurrence throughout memory-related brain structures. Thus, we analyzed synaptic markers, glial cells, and oxidative stress in the memory associated CA1 hippocampal region of APP/PS1 transgenic mice. Specifically, we assessed these targets in the immediate vicinity and distant from Aβ plaques. Hippocampal sections (coronal, 30 μm thick) from 1-year-old APP/PS1 mice and their wild type controls (n = 6/group) were fluorescently labeled for synapse density (synaptophysin), vesicular glutamate transporter (vGLUT2), DNA oxidation (8-hydroxyguanosine, 8-OHG), microglia (Iba-1), astrocytes (GFAP), neurons (NeuN), and Aβ plaques (X-34). Images were taken in the CA1 region with a conventional fluorescent microscope and analyzed using ImageJ. Fluorescence intensity was then quantified for each group. Next, the intensity profile was plotted for each fluorophore across the width of the Aβ plaques. There were relatively few amyloid plaques in the hippocampal CA1 region of APP/PS1 mice when compared to other regions of the hippocampus and cerebral cortex. Within the CA1 region, and in absence of Aβ, there was no pronounced change in synaptic density, presynaptic glutamate transporters, neurons, DNA oxidation, astrocytes, or microglia when compared to wild-type control. However, fluorescent intensity of some targets changed markedly along the perimeter of occasionally occurring Aβ plaques in the CA1 region. While the intensity profile of synaptophysin declined gradually towards the center of Aβ plaques, oxidative stress and microglia increased in the immediate surroundings of Aβ. Unexpectedly, also the intensity of presynaptic glutamate transporter vGLUT2 increased towards the core of the Aβ plaque. In summary, our data showed increased vesicular glutamate transporter, microglia, and oxidative stress confined to the vicinity of Aβ plaques in APP/PS1 mice. Increased vGLUT2 levels due to Aβ have been previously associated with hyperexcitability in AD. The parallel or subsequent decrease in synaptophysin is viewed as a compensatory response to limit hyperactivity. Together, the present study reveals important insights about the dynamics of cellular components in the vicinity of Aβ, and that aggregates of Aβ differentially affect presynaptic components important for synaptic transmission. NIH R15AG065927 (TDO &amp; DO), Truman State GIASR grant (TS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Moderate Physical Activity Increases the Expression of ADNP in Rat Brain.

Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity. Its mutation causes the autism-like ADNP syndrome (also called the Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders and motor dysfunctions. Similar to the ADNP syndrome, the ADNP haploinsufficient mouse shows low synapse density, leading to motor and cognitive ability delays. Moderate physical activity (PA) has several neuroprotective and cognitive benefits, promoting neuronal survival, differentiation, neurogenesis, and plasticity. Until now, no study has investigated the effect of moderate exercise on ADNP expression and distribution in the rat brain. The aim of the current investigation was to study the effects of moderate exercise on the ADNP expression and neuronal activation measured by the microtubule protein β-Tubulin III. In pursuit of this objective, twenty-four rats were selected and evenly distributed into two categories: sedentary control rats and rats exposed to moderate physical activity on a treadmill over a span of 12 weeks. Our results showed that moderate PA increases the expression of ADNP and β-Tubulin III in the dentate gyrus (DG) hippocampal region and cerebellum. Moreover, we found a co-localization of ADNP and β-Tubulin III in both DG and cerebellum, suggesting a direct association of ADNP with adult neuronal activation induced by moderate PA.

Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density.

Microglia sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, by removing apoptotic neurons, and by promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life by deletion of the fms-intronic regulatory element (FIRE) in the Csf1r locus. Surprisingly, young adult Csf1rΔFIRE/ΔFIRE mice display no changes in excitatory and inhibitory synapse number and spine density of CA1 hippocampal neurons compared with Csf1r+/+ littermates. However, CA1 neurons are less excitable, receive less CA3 excitatory input and show altered synaptic properties, but this does not affect novel object recognition. Cytokine profiling indicates an anti-inflammatory state along with increases in ApoE levels and reactive astrocytes containing synaptic markers in Csf1rΔFIRE/ΔFIRE mice. Notably, these changes in Csf1rΔFIRE/ΔFIRE mice closely resemble the effects of acute microglial depletion in adult mice after normal development. Our findings suggest that microglia are not mandatory for synaptic pruning, and that in their absence pruning can be achieved by other mechanisms.

Alteration of synaptic protein composition during developmental synapse maturation.

The postsynaptic density (PSD) is a collection of specialized proteins assembled beneath the postsynaptic membrane of dendritic spines. The PSD proteome comprises ~1000 proteins, including neurotransmitter receptors, scaffolding proteins and signalling enzymes. Many of these proteins have essential roles in synaptic function and plasticity. During brain development, changes are observed in synapse density and in the stability and shape of spines, reflecting the underlying molecular maturation of synapses. Synaptic protein composition changes in terms of protein abundance and the assembly of protein complexes, supercomplexes and the physical organization of the PSD. Here, we summarize the developmental alterations of postsynaptic protein composition during synapse maturation. We describe major PSD proteins involved in postsynaptic signalling that regulates synaptic plasticity and discuss the effect of altered expression of these proteins during development. We consider the abnormality of synaptic profiles and synaptic protein composition in the brain in neurodevelopmental disorders such as autism spectrum disorders. We also explain differences in synapse development between rodents and primates in terms of synaptic profiles and protein composition. Finally, we introduce recent findings related to synaptic diversity and nanoarchitecture and discuss their impact on future research. Synaptic protein composition can be considered a major determinant and marker of synapse maturation in normality and disease.