Academic literature on the topic 'Hippocampal neurons, synaptogenesis, Oligodendrocytes maturation'

Agrin, a 200 kDa extracellular matrix protein, participates in the maturation of the postsynaptic target at the neuromuscular junction. Although agrin has also been detected in central neurons, little is known about its role in the formation of their synapses. In the present study, the pattern of expression, localization and function of agrin in developing hippocampal neurons were analyzed. The results indicate that an increase in agrin protein levels precedes synaptogenesis in cultured hippocampal neurons. This increase in agrin expression is accompanied by its extracellular deposition along the distal third of the axon. To investigate whether agrin plays a role during synapse formation, its expression in cultured hippocampal neurons was suppressed by means of antisense oligonucleotide treatment. The suppression of agrin expression results in the impairment of dendritic development and the formation of fewer synapses than in non-treated or sense-treated neurons. Moreover, this decreased synaptic density is accompanied by a selective inhibition of the clustering of GABA receptors. These results lead to the conclusion that agrin may be an important regulator of the maturation of dendrites and synaptogenesis in central neurons.

Adult hippocampal neurogenesis is important for learning and memory, especially after a brain injury such as ischemia. Newborn hippocampal neurons contribute to memory performance by establishing functional synapses with target cells. This study demonstrated that the maturation of hippocampal neurons is enhanced by postischemia intermittent hypoxia (IH) intervention. The effects of IH intervention in cultured neurons were mediated by increased synaptogenesis, which was primarily regulated by brain-derived neurotrophic factor (BDNF)/PI3K/AKT. Hippocampal neo-neurons expressed BDNF and exhibited enhanced presynaptic function as indicated by increases in the pSynapsin expression, synaptophysin intensity, and postsynapse density following IH intervention after ischemia. Postischemia IH-induced hippocampal neo-neurons were affected by presynaptic activity, which reflected the dynamic plasticity of the glutamatergic receptors. These alterations were also associated with the alleviation of ischemia-induced long-term memory impairment. Our results suggest that postischemia IH intervention rescued ischemia-induced spatial learning and memory impairment by inducing hippocampal neurogenesis and functional synaptogenesis via BDNF expression.

Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.

Reductions in neurotrophic factors are implicated in synaptic dysfunction in the central nervous system, but exogenous neurotrophic factors with potential effects on neuritic regeneration and synaptic reconstruction could offer therapeutic and preventive strategies for treating memory-related neurological disorders. In an earlier effort to identify natural neurotrophic agents, we found that the ethanol extract of the edible marine alga Undaria pinnatifida (UPE) had promising effects on the neuritogenesis of cultured hippocampal neurons. Here, we further investigated the ability of UPE to promote spinogenesis and synaptogenesis in primary cultures of hippocampal neurons. It was found that UPE triggered significant increase in numbers of dendritic filopodia and spines, promoted the formation of excitatory and inhibitory synapses, and potentiated synaptic transmission by increasing the sizes of reserve vesicle pools at presynaptic terminals. These findings indicate a substantial role for UPE in the morphological and functional maturation of neurons and suggest that UPE is a possible therapeutic preventative measure and treatment for neurodegenerative diseases, such as those involving cognitive disorders and memory impairments.

ABSTRACT In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.

Abstract Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.

The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.

Silicon dioxide nanoparticles (SiO2-NPs) are among the most widely used nanoparticles because of their chemical-physical properties. Since most brain maturation occurs in the neonatal period in humans and many mammals, it is important to understand how NPs may affect this process. This study tested the hypothesis that SiO2-NPs from treated dams could affect the hippocampus of neonatal rats during lactation. Twenty-four pregnant rats, after delivery, were divided into three groups of control, SiO2-NPs (25 mg/kg) and SiO2-NPs (100 mg/kg). The rats were treated from 2nd to 21st days post-delivery by gavage and the effects of these NPs were evaluated in the offspring’s hippocampi to reveal the effects of maternal exposure to SiO2-NPs during lactation on the offspring’s hippocampi. The offspring in the SiO2-NPs groups had higher malondialdehyde concentration and lower antioxidant activity in the hippocampi than the non-treated control group. The mean number of doublecortin positive (DCX+) cells and synaptophysin expression in the hippocampi of the SiO2-NPs groups were significantly lower than the control group, whereas the mean number of dark neurons was significantly higher. Also, animals in the SiO2-NPs groups had a weak cognitive performance in adulthood. In conclusion, maternal exposure to SiO2-NPs via breastfeeding could affect offspring’s hippocampal neurogenesis and synaptogenesis, leading to impaired cognitive performance.

Background: Microglia play a pivotal role in maintaining homeostasis in complex brain environment. They first exist as amoeboid microglial cells (AMCs) in the developing brain, but with brain maturation, they transform into ramified microglial cells (RMCs). In pathological conditions, microglia are activated and have been classified into M1 and M2 phenotypes. The roles of AMCs, RMCs and M1/M2 microglia phenotypes especially in pathological conditions have been the focus of many recent studies. Methods: Here, we review the early development of the AMCs and RMCs and discuss their specific functions with reference to their anatomic locations, immunochemical coding etc. M1 and M2 microglia phenotypes in different neuropathological conditions are also reviewed. Results: Activated microglia are engaged in phagocytosis, production of proinflammatory mediators, trophic factors and synaptogenesis etc. Prolonged microglia activation, however, can cause damage to neurons and oligodendrocytes. The M1 and M2 phenotypes featured prominently in pathological conditions are discussed in depth. Experimental evidence suggests that microglia phenotype is being modulated by multiple factors including external and internal stimuli, local demands, epigenetic regulation, and herbal compounds. Conclusion: Prevailing views converge that M2 polarization is neuroprotective. Thus, proper therapeutic designs including the use of anti-inflammatory drugs, herbal agents may be beneficial in suppression of microglial activation, especially M1 phenotype, for amelioration of neuroinflammation in different neuropathological conditions. Finally, recent development of radioligands targeting 18 kDa translocator protein (TSPO) in activated microglia may hold great promises clinically for early detection of brain lesion with the positron emission tomography.

Heparan sulfates (HSs) are complex and highly active molecules that are required for synaptogenesis and long-term potentiation. A deficit in HSs leads to autistic phenotype in mice. Here, we investigated the long-term effect of heparinase I, which digests highly sulfated HSs, on the spontaneous bioelectrical activity of neuronal networks in developing primary hippocampal cultures. We found that chronic heparinase treatment led to a significant reduction of the mean firing rate of neurons, particularly during the period of maximal neuronal activity. Furthermore, firing pattern in heparinase-treated cultures often appeared as epileptiform bursts, with long periods of inactivity between them. These changes in network activity were accompanied by an increase in the frequency and amplitude of miniature postsynaptic excitatory currents, which could be described by a linear up-scaling of current amplitudes. Biochemically, we observed an upregulation in the expression of the glutamate receptor subunit GluA1, but not GluA2, and a strong increase in autophosphorylation of α and β Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), without changes in the levels of kinase expression. These data suggest that a deficit in HSs triggers homeostatic synaptic plasticity and drastically affects functional maturation of neural network.

Bone marrow-derived mesenchymal stem cells (MSCs) account for a small population of cells of the non-hematopoietic component of bone marrow. MSCs are multipotent stem cells endowed with neurotrophic potential combined to immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. Although the mechanisms by which they act are still largely unknown, trans-differentiation, paracrine and autocrine actions have been hypothesized. Here we focus on the study of the effects exerted by rat MSCs on CNS neurons and oligodendrocytes by using a simplified in vitro co-culture system that precludes any direct contact between different cell types. The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs by themselves, efficiently support morphological and functional neuronal differentiation. Our observations demonstrate that MSCs selectively and directly increased hippocampal GABAergic presynapses and inhibitory transmission. In fact, this increment correlated to a higher expression of the potassium/chloride KCC2 cotransporter and to an enhancement of both the frequency and the amplitude of mIPSC and sIPSC. The decreased of GABA synapses following the treatment with a widely used Trk-neurotrophin receptor blocker, K252a, and the more specific TrkB receptor bodies prompt for the involvement of the brain derived neurotrophic factor (BDNF) in mediating such effects. The involvement of this neurotrophin is also strengthened by test ELISA on the culture medium collected from MSC-neuron co-cultures in which an higher BDNF concentration was detected, when compared to astrocyte-neuron co-cultures. The results obtained indicate that MSC-secreted factors induce glial-dependent neuronal survival and directly trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could cooperate in CNS repair. Additionally, MSCs have been described to improve the clinical course of some demyelinating pathologies and to promote tissue repair through immunological mechanisms and neuroprotective effects. Following these evidences we performed in vitro and in vivo experiments to assess whether MSCs exert their actions through the support of oligodendrocytes (OLs), the myelinating CNS cells, and participate in the regulation of their proliferation and maturation. Through the analysis of specific proteins typically used as markers of the different stages of proliferation, maturation and differentiation (specifically, the membrane glycoprotein O4, the proteoglycan NG2 and myelin basic protein MBP, respectively), it has been noticed that MSCs are capable to prolong the proliferation phase of OPCs and also to anticipate OL differentiation, with respect to standard astrocyte/OL co-cultures. Moreover we investigated a possible molecular mechanism underlying these phenomena focusing on neurotrophin pathways. Trk receptors activation was analyzed in order to find out a possible role of neurotrophins in MSC-mediated effects on OLs, as it happens in neuronal cultures. We focused on the changes in the phosphorylation level of ERK (Extracellular signaling-regulated kinases), one of the activated effectors by TrK receptors. Our observations show that, in OLs co-cultured with MSCs, ERK is highly phosphorylated with respect to astrocyte/OL co-cultures, suggesting a MSC-induced activation of the pathways regulated by this protein. These data, although preliminary, suggest that MSCs positively act on the regulation of proliferation and maturation of OLs and, due to the observed effects on the regulation of synaptogenesis (see above), make these cells an interesting model for the identification of molecules involved in MSC neuroprotective processes. This may open new therapeutic approaches in the treatment of neurodegenerative diseases involving not only a synaptic imbalance, as it happens in various forms of epilepsy, but also in demyelinating diseases. Thus, in this research project, we aimed at characterising the molecular mechanisms underlying MSC actions that could participate in the recovery of neurological disorders or demyelinating pathologies.