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Neuroplasticity refers to the nervous system's ability to modify its structure and function in response to intrinsic and extrinsic stimuli. Impairments in this capacity are associated with various neurological disorders, underscoring the need for therapies that preserve or enhance neuronal plasticity. Medicinal plants offer a promising source of bioactive compounds with neuroplastic properties and neuroprotective potential. In this work, we report the chemical and neuroplastic properties of , a medicinal native plant from America. Ethanolic extracts (EtOH) of leaves and stems, along with subfractionated ethyl acetate (EtOAc) and hydroethanolic (H O:EtOH) extracts, were analyzed using High-Performance Thin-Layer Chromatography (HPTLC) and Ultra-Performance Liquid Chromatography coupled with a Diode Array Detector (UPLC-DAD), revealing the presence of 14 phenolic acids, 6 flavonoids, and triterpene. Additionally, functional analysis using Sholl analysis showed that the EtOAc fraction of significantly enhanced structural plasticity in vitro, increasing both dendritic branching and dendrite length at concentrations between 0.03 and 1 μg mL , likely through the activation PI3K/Akt and ERK1/2 signaling pathways. Together, our results suggest that contains bioactive polar metabolites capable of inducing neuronal structural plasticity.

Neuronal activity orchestrates the proper development of the neuronal circuitry by regulating both transcriptional and post‐transcriptional gene expression programmes. How these programmes are coordinated, however, is largely unknown. We found that the transcription of miR379–410, a large cluster of brain‐specific microRNAs (miRNAs), is induced by increasing neuronal activity in primary rat neurons. Results from chromatin immunoprecipitation and luciferase reporter assays suggest that binding of the transcription factor myocyte enhancing factor 2 (Mef2) upstream of miR379–410 is necessary and sufficient for activity‐dependent transcription of the cluster. Mef2‐induced expression of at least three individual miRNAs of the miR379–410 cluster is required for activity‐dependent dendritic outgrowth of hippocampal neurons. One of these miRNAs, the dendritic miR‐134, promotes outgrowth by inhibiting translation of the mRNA encoding for the translational repressor Pumilio2. In summary, we have described a novel regulatory pathway that couples activity‐dependent transcription to miRNA‐dependent translational control of gene expression during neuronal development.

The establishment of neuronal circuits requires neurons to develop and maintain appropriate connections with cellular partners in and out the central nervous system. These phenomena include elaboration of dendritic arborization and formation of synaptic contacts, initially made in excess. Subsequently, refinement occurs, and pruning takes places both at axonal and synaptic level, defining a homeostatic balance maintained throughout the lifespan. All these events require genetic regulations which happens cell-autonomously and are strongly influenced by environmental factors. This review aims to discuss the involvement of guidance cues from the Semaphorin family.

The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits.

Microtubules (MTs) are dynamic components of the cell cytoskeleton involved in several cellular functions, such as structural support, migration and intracellular trafficking. Despite their high similarity, MTs have functional heterogeneity that is generated by the incorporation into the MT lattice of different tubulin gene products and by their post-translational modifications (PTMs). Such regulations, besides modulating the tubulin composition of MTs, create on their surface a “biochemical code” that is translated, through the action of protein effectors, into specific MT-based functions. This code, known as “tubulin code”, plays an important role in neuronal cells, whose highly specialized morphologies and activities depend on the correct functioning of the MT cytoskeleton and on its interplay with a myriad of MT-interacting proteins. In recent years, a growing number of mutations in genes encoding for tubulins, MT-interacting proteins and enzymes that post-translationally modify MTs, which are the main players of the tubulin code, have been linked to neurodegenerative processes or abnormalities in neural migration, differentiation and connectivity. Nevertheless, the exact molecular mechanisms through which the cell writes and, downstream, MT-interacting proteins decipher the tubulin code are still largely uncharted. The purpose of this review is to describe the molecular determinants and the readout mechanisms of the tubulin code, and briefly elucidate how they coordinate MT behavior during critical neuronal events, such as neuron migration, maturation and axonal transport.

New neurons in the adult dentate gyrus are widely held to incorporate into hippocampal circuitry via a stereotypical sequence of morphological and physiological transitions, yet the molecular control over this process remains unclear. We studied the role of brain-derived neurotrophic factor (BDNF)/TrkB signaling in adult neurogenesis by deleting the full-length TrkB via Cre expression within adult progenitors in TrkBlox/lox mice. By 4 weeks after deletion, the growth of dendrites and spines is reduced in adult-born neurons demonstrating that TrkB is required to create the basic organization of synaptic connections. Later, when new neurons normally display facilitated synaptic plasticity and become preferentially recruited into functional networks, lack of TrkB results in impaired neurogenesis-dependent long-term potentiation and cell survival becomes compromised. Because of the specific lack of TrkB signaling in recently generated neurons a remarkably increased anxiety-like behavior was observed in mice carrying the mutation, emphasizing the contribution of adult neurogenesis in regulating mood-related behavior.

Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.

The activation of mAChR on subplate neurons has been shown to trigger oscillatory glutamatergic network activity in early postnatal neocortex. Here, we explored the long-term consequences of subplate activation on the differentiation of cortical neurons. Stimulating newborn somatosensory and visual cortex ex vivo and organotypic cortex cultures (OTCs) of the visual cortex with carbachol (CCH) led to an upregulation of Bdnf and Zif-268 . In OTCs, the stimulation increased the amplitude and frequency of calcium events in the gray matter layers at DIV 3–5. At DIV 5, an acute stimulation rapidly activates p21ras; increases ERK phosphorylation; induces Bdnf, c-Fos, and Zif-268 expression; and increases GluN1, GluN2A, GluN2B, PSD-95, GAD-65, and synaptophysin protein expression. The NMDA receptors were functional, as shown by enhanced ligand-induced dendritic injury. Repeated DIV 1–5 mAChR activation increased, at DIV 10, the expression of GluN2A, of an essential protein of the inhibitory presynapse, VGAT, and the basket-cell-specific presynaptic calcium sensor synaptotagmin-2. Furthermore, it increased the frequency of interneuronal calcium events at DIV 10–15, dendritic length of basket cells, and accelerated the local arborization of basket cell axons at DIV 15. The results suggest that temporally limited mAChR-mediated activation of subplate neurons evokes glutamatergic network activity, which, gradually over the following weeks, promotes cortical circuit development. Specifically, it enhances the expression of excitatory and inhibitory synaptic proteins and accelerates the morphological and functional maturation of basket cells, highlighting the cholinergic input to subplate neurons as a critical regulator of interneuron development.

A battery of genetically encoded calcium indicators (GECIs) with different binding kinetics and calcium affinities was developed over the recent years to permit long-term calcium imaging. GECIs are calcium buffers and therefore, expression of GECIs may interfere with calcium homeostasis and signaling pathways important for neuronal differentiation and survival. Our objective was to investigate if biolistically induced expression of five commonly used GECIs at two postnatal time points (days 14 and 22-25) could affect the morphological maturation of cortical neurons in organotypic slice cultures of rat visual cortex. Expression of GCaMP3 in both time windows, and of GCaMP5G and TN-XXL in the later time window impaired apical and /or basal dendrite growth of pyramidal neurons. With time, the proportion of GECI transfectants with nuclear filling increased, but only prolonged expression of TN-XXL caused higher levels of neurodegeneration. In multipolar interneurons, only GCaMP3 evoked a transient growth delay during the early time window. GCaMP6m and GCaMP6m-XC were quite “neuron-friendly”. Since growth-impaired neurons might not have the physiological responses typical of age-matched wildtype neurons the results obtained after prolonged developmental expression of certain GECIs might need to be interpreted with caution.

The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.