Plasticity In Hippocampal Neurons Research Articles

Sodium channel endocytosis drives axon initial segment plasticity.

Activity-dependent plasticity of the axon initial segment (AIS) endows neurons with the ability to adapt action potential output to changes in network activity. Action potential initiation at the AIS highly depends on the clustering of voltage-gated sodium channels, but the molecular mechanisms regulating their plasticity remain largely unknown. Here, we developed genetic tools to label endogenous sodium channels and their scaffolding protein, to reveal their nanoscale organization and longitudinally image AIS plasticity in hippocampal neurons in slices and primary cultures. We find that N-methyl-d-aspartate receptor activation causes both long-term synaptic depression and rapid internalization of AIS sodium channels within minutes. The clathrin-mediated endocytosis of sodium channels at the distal AIS increases the threshold for action potential generation. These data reveal a fundamental mechanism for rapid activity-dependent AIS reorganization and suggests that plasticity of intrinsic excitability shares conserved features with synaptic plasticity.

Transcriptome analysis of the effects of maternal fructose exposure during gestation and lactation on the cytoskeleton of offspring hippocampus

Excessive fructose consumption poses a public health concern. Maternal fructose overconsumption impairs offspring hippocampal function, indicating hippocampal sensitivity to fructose. The hippocampus is the vital for spatial learning and memory, and the cytoskeletal structure is crucial for hippocampal neuronal plasticity. The Rho GTPase is a key regulator of neuronal cytoskeleton formation, with RhoA protein governing neuronal growth and development. The RhoA/ROCK2 pathway affects myosin light chain phosphorylation, leading to cytoskeletal reorganization, actin cytoskeleton changes, and neurite retraction. However, the effects of maternal fructose exposure during gestation and lactation on the offspring's neural cytoskeleton remain unclear. We established maternal fructose exposure models during gestation and lactation, assessing fasting blood glucose levels in offspring confirm model effectiveness. Whole transcriptome sequencing examined offspring hippocampal developmental programming. Immunofluorescence and Western blot analyses assessed RhoA/ROCK2 pathway expression changes in the hippocampus, with PCR validating transcriptome sequencing results. Transcriptome sequencing identified 193 and 298 differentially expressed genes in the control, 13% fructose, and 40% fructose groups, respectively. GO and KEGG analyses revealed significant changes related to neural development, learning memory, and cytoskeleton in both fructose-exposed groups. GSEA indicated substantial cytoskeleton-related alterations in the offspring. Immunofluorescence demonstrated significant CRMP2 protein down-regulation in both fructose-exposed groups. Western blotting showed significantly higher expression of RhoA, ROCK2, p-ROCK2, and p-MLC2 in the fructose-exposed groups (P < 0.05). Maternal high-fructose exposure significantly impacts gene expression in offspring. These alterations may influence hippocampal neurodevelopment by up-regulating the RhoA/ROCK2 pathway, leading to cytoskeletal damage and axon growth inhibition.

A critical role for CaMKII in behavioral timescale synaptic plasticity in hippocampal CA1 pyramidal neurons.

Behavioral timescale synaptic plasticity (BTSP) is a type of non-Hebbian synaptic plasticity reported to underlie place field formation. Despite this important function, the molecular mechanisms underlying BTSP are poorly understood. The α-calcium-calmodulin-dependent protein kinase II (αCaMKII) is activated by synaptic transmission-mediated calcium influx, and its subsequent phosphorylation is central to synaptic plasticity. Because the activity of αCaMKII is known to outlast the event triggering phosphorylation, we hypothesized that it could mediate the extended timescale of BTSP. To examine the role of αCaMKII in BTSP, we performed whole-cell in vivo and in vitro recordings in CA1 pyramidal neurons from mice engineered with a point mutation at the autophosphorylation site (T286A) causing accelerated signaling kinetics. Here, we demonstrate a profound deficit in synaptic plasticity, strongly suggesting that αCaMKII signaling is required for BTSP. This study elucidates part of the molecular mechanism of BTSP and provides insight into the function of αCaMKII in place cell formation and ultimately learning and memory.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects.

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

A comparison of the impact on neuronal transcriptome and cognition of rAAV5 transduction with three different doses in the mouse hippocampus.

Recombinant adeno-associated viruses (rAAVs) are widely used in genetic therapeutics. AAV5 has shown superior transduction efficiency, targeting neurons and glial cells in primate brains. Nonetheless, the comprehensive impact of AAV5 transduction on molecular and behavioral alterations remains unexplored. This study focuses on evaluating the effects of AAV5 transduction in the hippocampus, a critical region for memory formation and emotional processes. In this experiment, fluorescence-activated cell sorting (FACS) was utilized to isolate the mCherry-labeled pyramidal neurons in the hippocampus of CaMkIIα-cre mice following three different doses rAAV5-mCherry infusion after 3 weeks, which were then subjected to RNA sequencing (RNA-seq) to assess gene expression profiles. The cytokines concentration, mRNA expression, and glial response in hippocampi were confirmed by ELASA, digital droplet PCR and immunohistochemistry respectively. Locomotion and anxiety-like behaviors were elevated by Open Field Test and Elevated Plus Maze Test, while the Y-Maze were used to assessed spatial working memory. Recognition memory and fear responses were examined by the Novel Object Recognition Test and Fear Conditioning Test, respectively. We found that 2.88 × 1010 v.g rAAV5 transduction significantly upregulated genes related to the immune response and apoptosis, and downregulated genes associated with mitochondrial function and synaptic plasticity in hippocampal pyramidal neurons, while did not induce neuronal loss and gliosis compared with 2.88 × 109 v.g and 2.88 × 108 v.g. Furthermore, the same doses impaired working memory and contextual fear memory, without effects on locomotion and anxiety-related behaviors. Our findings highlight the detrimental impact of high-dose administration compared to median-dose or low-dose, resulting in increased neural vulnerability and impaired memory. Therefore, when considering the expression effectiveness of exogenous genes, it is crucial to also take potential side effects into account in clinical settings. However, the precise molecular mechanisms underlying these drawbacks of high-dose rAAV5-mCherry still require further investigation in future studies.

Treadmill Exercise Alleviates Cognition Disorder by Activating the FNDC5: Dual Role of Integrin αV/β5 in Parkinson's Disease.

Parkinson's disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from the substantia nigra to the hippocampus are critical in regulating hippocampal plasticity. Recently, aerobic exercise has been recognized as an effective therapeutic strategy for enhancing plasticity through the secretion of various muscle factors. The exact role of FNDC5-an upregulated, newly identified myokine produced after exercise-in mediating hippocampal plasticity and regional dopaminergic projections in PD-CI remains unclear. In this study, the effect of treadmill exercise on hippocampal synaptic plasticity was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD models. The results showed that treadmill exercise substantially alleviated the motor dysfunction, cognition disorder, and dopaminergic neuron degeneration induced by MPTP. Here, we discovered that the quadriceps, serum, and brain FNDC5 levels were lower in PD mice and that intervention with treadmill exercise restored FNDC5 levels. Moreover, treadmill exercise enhanced the synaptic plasticity of hippocampal pyramidal neurons via increased dopamine levels and BDNF in the PD mice. The direct protective effect of FNDC5 is achieved by promoting the secretion of BDNF in the hippocampal neurons via binding the integrin αVβ5 receptor, thereby improving synaptic plasticity. Regarding the indirect protection effect, FNDC5 promotes the dopaminergic connection from the substantia nigra to the hippocampus by mediating the interaction between the integrin αVβ5 of the hippocampal neurons and the CD90 molecules on the membrane of dopaminergic terminals. Our findings demonstrated that treadmill exercise could effectively alleviate cognitive disorders via the activation of the FNDC5-BDNF pathway and enhance the dopaminergic synaptic connection from SNpc to the hippocampus in the MPTP-induced chronic PD model.

Chronic Mycobacterium avium infection differentially affects the cytokine expression profile of three mouse strains, but has no effect on behavior

One of the most remarkable findings in the immunology and neuroscience fields was the discovery of the bidirectional interaction between the immune and the central nervous systems. This interplay is tightly regulated to maintain homeostasis in physiological conditions. Disruption in this interplay has been suggested to be associated with several neuropsychiatric disorders. Most studies addressing the impact of an immune system disruption on behavioral alterations focus on acute pro-inflammatory responses. However, chronic infections are highly prevalent and associated with an altered cytokine milieu that persists over time. Studies addressing the potential effect of mycobacterial infections on mood behavior originated discordant results and this relationship needs to be further addressed. To increase our understanding on the effect of chronic infections on the central nervous system, we evaluated the role of Mycobacterium avium infection. A model of peripheral chronic infection with M. avium in female from three mouse strains (Balb/c, C57BL/6, and CD-1) was used. The effect of the infection was evaluated in the cytokine expression profile (spleen and hippocampus), hippocampal cell proliferation, neuronal plasticity, serum corticosterone production and mood behavior. The results show that M. avium peripheral chronic infection induces alterations not just in the peripheral immune system but also in the central nervous system, namely in the hippocampus. Interestingly, the cytokine expression profile alterations vary between mouse strains, and are not accompanied by hippocampal cell proliferation or neuronal plasticity changes. Accordingly, no differences were observed in locomotor, anxious and depressive-like behaviors, in any of the mouse strains used. We conclude that the M. avium 2447 infection-induced alterations in the cytokine expression profile, both in the periphery and the hippocampus, are insufficient to alter hippocampal plasticity and behavior.

Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons.

Neurons are polarized cells, and their ability to change their morphology has a functional implication in the development and plasticity of the nervous system in order to establish new connections. Extracellular factors strongly influence neuronal shape and connectivity. For instance, the developmental actions of estradiol on hippocampal neurons are well characterized, and we have demonstrated in previous studies that Ngn3 mediates these actions. On the other hand, Kif21B regulates microtubule dynamics and carries out retrograde transport of the TrkB/brain-derived neurotrophic factor (BDNF) complex, essential for neuronal development. In the present study, we assessed the involvement of kinesin Kif21B in the estradiol-dependent signaling mechanisms to regulate neuritogenesis through cultured mouse hippocampal neurons. We show that estradiol treatment increases BDNF expression, and estradiol and BDNF modify neuron morphology through TrkB signaling. Treatment with K252a, a TrkB inhibitor, decreases dendrite branching without affecting axonal length, whereas. Combined with estradiol or BDNF, it blocks their effects on axons but not dendrites. Notably, the downregulation of Kif21B abolishes the actions of estradiol and BDNF in both the axon and dendrites. In addition, Kif21B silencing also decreases Ngn3 expression, and downregulation of Ngn3 blocks the effect of BDNF on neuron morphology. These results suggest that Kif21B is required for the effects of estradiol and BDNF on neuronal morphology, but phosphorylation-mediated activation of TrkB is essential only for axonal growth. Our results show that the Estradiol/BDNF/TrkB/Kif21B/Ngn3 is a new and essential pathway mediating hippocampal neuron development.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice

BackgroundSepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. MethodLipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-μm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. ResultsIntracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml−1 to 382 [14] pg ml−1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. ConclusionsSystemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.

A Review of Aspects of Synaptic Plasticity in Hippocampus via mT Extremely Low-Frequency Magnetic Fields.

The subthreshold magnetic modulation technique stimulates cells with mT extremely low-frequency magnetic fields (ELF-MFs), which are insufficient to induce neuronal action potentials. Although they cannot directly induce resting neurons to discharge, mT magnetic stimulation can regulate the excitability of the nervous system, which regulates learning and memory by some unknown mechanisms. Herein, we describe the regulation of mT ELF-MFs with different parameters on synaptic plasticity in hippocampal neurons. Additionally, we summarize the latest research on the possible mechanism of the effect of ELF-MFs on synaptic plasticity. Some studies have shown that ELF-MFs are able to inhibit long-term potentiation (LTP) by increasing concentration of intracellular Ca2+ concentration ([Ca2+ ]i ), as well as concentration of reactive oxygen species. The research in this paper has significance for the comprehensive understanding of relevant neurological mechanisms of learning and memory by mT ELF-MFs stimulation. However, more high-quality research is necessary to determine the regulatory mechanism of mT ELF-MFs on synaptic plasticity in order to optimize this technique as a treatment for neurological diseases. © 2023 Bioelectromagnetics Society.

Local CRF and oxytocin receptors correlate with female experience-driven avoidance change and hippocampal neuronal plasticity

Understanding how experiences affect females' behaviors and neuronal plasticity is essential for uncovering the mechanism of neurodevelopmental disorders. The study explored how neonatal maternal deprivation (MD) and post-weaning environmental enrichment (EE) impacted the CA1 and DG's neuronal plasticity in the dorsal hippocampus, and its relationships with passive avoidance, local corticotrophin-releasing factor (CRF) levels, and oxytocin receptor (OTR) levels in female BALB/c mice. The results showed that MD damaged passive avoidance induced by foot shock and hotness, and EE restored it partially. In the CA1, MD raised CRF levels and OTR levels. Parallelly, MD increased synaptic connection levels but reduced the branches' numbers of pyramidal neurons. Meanwhile, in the DG, MD increased OTR levels but lowered CRF levels, DNA levels, and spine densities. EE did not change the CA1 and DG's CRF and OTR levels. However, EE added DG's dendrites of granular cells. The additive of MD and EE raised CA1's synaptophysin and DG's postsynaptic density protein-95 and OTR levels, and meanwhile, shaped avoidance behaviors primarily similar to the control. The results suggest that experience-driven avoidance change and hippocampal neuronal plasticity are associated with local CRF and OTR levels in female mice.

Chlorpyrifos-induced dysregulation of synaptic plasticity in rat hippocampal neurons

Chlorpyrifos (CPF) is a widely used organophosphorus pesticide. Increasing evidence has shown that exposure to CPF in early life might induce neurodevelopmental disorders, but the pathogenesis remains uncertain. Synaptic plasticity plays a crucial role in neurodevelopment. This study aimed to investigate the effect of CPF on synaptic plasticity in hippocampal neurons and establish the cellular mechanism underlying these effects. Using CPF-exposed rat and primary hippocampal neurons model, we analyzed the impact of CPF on the synaptic morphology, the expression level of a presynaptic protein, a postsynaptic protein and ionotropic glutamate receptors (iGluRs), as well as the effects on the Wnt/β-catenin pathway. We found that the synapses were shortened, the spines were decreased, and the expression of synaptophysin (Syp), postsynaptic density-95 (PSD-95), GluN1, GluA1 and Wnt7a, as well as active β-catenin in primary hippocampal neurons was decreased. Our study suggests that CPF exposure induced dysregulation of synaptic plasticity in rat hippocampal neurons, which might provide novel information regarding the mechanism of CPF-induced neurodevelopmental disorders.

Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis.

Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer's disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice's spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.

LOV2-based photoactivatable CaMKII and its application to single synapses: Local Optogenetics.

Optogenetic techniques offer a high spatiotemporal resolution to manipulate cellular activity. For instance, Channelrhodopsin-2 with global light illumination is the most widely used to control neuronal activity at the cellular level. However, the cellular scale is much larger than the diffraction limit of light (<1 μm) and does not fully exploit the features of the "high spatial resolution" of optogenetics. For instance, until recently, there were no optogenetic methods to induce synaptic plasticity at the level of single synapses. To address this, we developed an optogenetic tool named photoactivatable CaMKII (paCaMKII) by fusing a light-sensitive domain (LOV2) to CaMKIIα, which is a protein abundantly expressed in neurons of the cerebrum and hippocampus and essential for synaptic plasticity. Combining photoactivatable CaMKII with two-photon excitation, we successfully activated it in single spines, inducing synaptic plasticity (long-term potentiation) in hippocampal neurons. We refer to this method as "Local Optogenetics", which involves the local activation of molecules and measurement of cellular responses. In this review, we will discuss the characteristics of LOV2, the recent development of its derivatives, and the development and application of paCaMKII.

β-Hydroxybutyric acid improves cognitive function in a model of heat stress by promoting adult hippocampal neurogenesis

Heat stress has multiple potential effects on the brain, such as neuroinflammation, neurogenesis defects, and cognitive impairment. β-hydroxybutyric acid (BHBA) has been demonstrated to play neuroprotective roles in various models of neurological diseases. In the present study, we investigated the efficacy of BHBA in alleviating heat stress-induced impairments of adult hippocampal neurogenesis and cognitive function, as well as the underlying mechanisms. Mice were exposed to 43 ℃ for 15 min for 14 days after administration with saline, BHBA, or minocycline. Here, we showed for the first time that BHBA normalized memory ability in the heat stress-treated mice and attenuated heat stress-impaired hippocampal neurogenesis. Consistently, BHBA noticeably improved the synaptic plasticity in the heat stress-treated hippocampal neurons by inhibiting the decrease of synapse-associated proteins and the density of dendritic spines. Moreover, BHBA inhibited the expression of cleaved caspase-3 by suppressing endoplasmic reticulum (ER) stress, and increased the expression of brain-derived neurotrophic factor (BDNF) in the heat stress-treated hippocampus by activating the protein kinase B (Akt)/cAMP response element binding protein (CREB) and methyl-CpG binding protein 2 (MeCP2) pathways. These findings indicate that BHBA is a potential agent for improving cognitive functions in heat stress-treated mice. The action may be mediated by ER stress, and Akt-CREB-BDNF and MeCP2 pathways to improve adult hippocampal neurogenesis and synaptic plasticity.

Effects of transcranial direct current stimulation on brain cytokine levels in rats.

Transcranial direct current stimulation (tDCS) has shown therapeutic potential to mitigate symptoms of various neurological disorders. Studies from our group and others used rodent models to demonstrate that tDCS modulates synaptic plasticity. We previously showed that 30 min of 0.25 mA tDCS administered to rats induced significant enhancement in the synaptic plasticity of hippocampal neurons. It has also been shown that tDCS induces expression of proteins known to mediate synaptic plasticity. This increase in synaptic plasticity may underly the observed therapeutic benefits of tDCS. However, the anti-inflammatory benefits of tDCS have not been thoroughly elucidated. Here we report that three sessions of tDCS spaced 1-3 weeks apart can significantly reduce levels of several inflammatory cytokines in brains of healthy rats. Rats receiving tDCS experienced enhanced synaptic plasticity without detectable improvement in behavioral tests or significant changes in astrocyte activation. The tDCS-mediated reduction in inflammatory cytokine levels supports the potential use of tDCS as a countermeasure against inflammation and offers additional support for the hypothesis that cytokines contribute to the modulation of synaptic plasticity.

RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease.

RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H-Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long-term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

Involvement of CaV 2.2 channels and α2 δ-1 in homeostatic synaptic plasticity in cultured hippocampal neurons.

In the mammalian brain, presynaptic CaV 2 channels play a pivotal role in synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone of presynaptic terminals. However, the distribution and modulation of CaV 2.2 channels at plastic hippocampal synapses remains to be elucidated. Here, we assess CaV 2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. We show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV 2.2 channels at the presynaptic site. This work focused further on the role of α2 δ-1subunits, important regulators of synaptic transmission and CaV 2.2 channel abundance at the presynaptic membrane. We found that α2 δ-1 overexpression reduces the contribution of CaV 2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Levels of endogenous α2 δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2 δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV 2.2 channels and novel roles for α2 δ-1 during synaptic plastic adaptation. KEY POINTS: The roles of CaV 2.2 channels and α2 δ-1 in homeostatic synaptic plasticity in hippocampal neurons in culture were examined. Chronic silencing of neuronal activity resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV 2.2 channels at presynaptic sites. The level of endogenous α2 δ-1 decreased during homeostatic synaptic plasticity, whereas overexpression of α2 δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV 2.2 channels and novel roles for α2 δ-1 during synaptic plastic adaptation.

β‐secretase inhibition prevents structural spine plasticity deficits in AppNL‐G‐F mice

AbstractBackgroundBACE1‐inhibitor trials for the treatment of Alzheimer´s Disease (AD) have failed due to insufficient efficacy or side effects like cognitive worsening. However, the scientific evidence to date suggests that BACE1‐inhibition could be an effective preventative measure if applied early enough and in the correct dose. Preclinical studies have associated strong BACE1‐inhibition with decreased dendritic spine density in the cerebral cortex of wildtype mice (GFP‐M) only.MethodWe investigated dose‐dependent effects of BACE1‐inhibition on hippocampal dendritic spine dynamics in the APP knock‐in mouse line for the first time. We conducted in vivo two‐photon microscopy in the stratum oriens of hippocampal CA1 neurons in 3.5‐month‐old AppNL‐G‐FGFP‐M mice over 6 weeks to monitor the effect of Bace1 inhibition (NB‐360) in low and high doses on dendritic spine plasticity.ResultsStructural spine plasticity is already impaired in CA1 neurons in untreated AppNL‐G‐F mice of this early age. Interestingly, prolonged high‐dose but not low‐dose BACE1‐inhibition was found to enhance spine formation and did not cause spine loss as observed in wildtype control mice.ConclusionIn an early stage of amyloid pathology in a transgenic beta‐amyloid mouse model, BACE1‐inhibition successfully holds the progressive changes in dendritic spine plasticity in hippocampal CA1 neurons.

Hippocampal microRNA-26a-3p deficit contributes to neuroinflammation and behavioral disorders via p38 MAPK signaling pathway in rats

BackgroundNeuronal injury is considered a critical risk factor in the pathogenesis of most neurological and neuropsychiatric diseases. However, the underlying molecular mechanisms and identification of potential therapeutic targets for preventing neuronal injury associated with brain function remain largely uncharacterized. Therefore, identifying neural mechanisms would put new insights into the progression of this condition and provide novel therapeutic strategies for the treatment of these diseases.MethodsStereotactic injection of AAV virus was used to knock-down the miR-26a-3p within hippocampus of rats. Behavioral changes was detected by open field test (OFT), elevated plus maze (EPM), forced swim test (FST) and sucrose preference test (SPT). The inflammatory cytokines and related proteins were verified by real-time quantitative PCR, immunoblotting or immunofluorescence assay. Golgi staining and electron microscopy analysis was used to observe the dendritic spine, synapse and ultrastructural pathology. SB203580 (0.5 mg/kg) were administered daily to prevent p38 MAPK via an intraperitoneal (i.p.) injection. Finally, electrophysiological method was used to examine the synaptic transmission via whole-cell patch-clamp recording.ResultsHere, we showed that miR-26a-3p deficiency within hippocampal regions leads to the activation of microglia, increased level of pro-inflammatory cytokines and behavioral disorders in rats, effects which appear to be mediated by directly targeting the p38 mitogen-activated protein kinase (MAPK)–NF-κB signaling pathway. Specifically, we found that the enhanced glia-activation may consequently result in neuronal deterioration that mainly presented as the dysregulation of structural and functional plasticity in hippocampal neurons. In contrast, preventing p38 pathway by SB203580 significantly ameliorated abnormal behavioral phenotypes and neuronal jury resulting from miR-26a-3p knock-down.ConclusionThese results suggest that the normal expression of miR-26a-3p exerts neuroprotective effects via suppressing neural abnormality and maintaining neuroplasticity to against behavioral disorders in rats. These effects appear to involve a down-regulation of p38 MAPK-NF-κB signaling within the hippocampal region. Taken together, these findings provide evidence that miR-26a-3p can function as a critical factor in regulating neural activity and suggest that the maintaining of normal structure and function of neurons might be a potential therapeutic strategy in the treatment of neurological disorders.Graphical