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Neurochemical Research May 2024There is growing evidence showing that adiponectin (APN) can improve Alzheimer's disease(AD)-like pathological changes by improving insulin resistance. However, the role...
There is growing evidence showing that adiponectin (APN) can improve Alzheimer's disease(AD)-like pathological changes by improving insulin resistance. However, the role of AdipoRon (an Adiponectin receptor agonist) on synaptic plasticity and cognitive dysfunction in the early stages of type 2 diabetes mellitus(T2DM) remains unknown. In this study, we investigated the neuroprotective effect and the molecular mechanism underlying the effect of AdipoRon in T2DM mice. We found that AdipoRon significantly restored the cognitive deficits in T2DM mice, including shorter escape latency, more crossing times, increased distances, and percentage of time in the target quadrant. In addition, AdipoRon treatment up-regulated synaptic proteins (PSD95, SYN, GAP43, and SYP), increased the number of hippocampal synapses and attenuated synaptic damage, including the length, the number and the density of dendritic spines in CA1 and DG regions. Furthermore, AdipoRon attenuated Tau phosphorylation at multiple AD-related sites (p-tau 205, p-tau 396, p-tau 404) by promoting AdipoR expression and activating the AMPK/mTOR pathway. Our data suggests that AdipoRon exerts neuroprotective effects on the T2DM mice, which may be mediated by the activation of the AdipoR/AMPK/mTOR signaling pathway.
PubMed: 38819697
DOI: 10.1007/s11064-024-04162-4 -
Epilepsia May 2024Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and...
Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.
OBJECTIVE
Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV neurons occur in the hippocampus of MeCP2 mice and whether these morphological changes contribute to epilepsy susceptibility.
METHODS
We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV neurons for structural analysis.
RESULTS
Epilepsy susceptibility was increased in MeCP2 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2 mice. The dendritic complexity in MeCP2 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2 mice.
SIGNIFICANCE
Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.
PubMed: 38819633
DOI: 10.1111/epi.18027 -
Neuroreport Jul 2024Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can...
Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.
Topics: Animals; Melatonin; Cisplatin; Dendritic Spines; Male; Hippocampus; Rats; Cognitive Dysfunction; Antineoplastic Agents; Neuroprotective Agents; Antioxidants; Rats, Wistar; Chemotherapy-Related Cognitive Impairment; Memory, Short-Term
PubMed: 38813907
DOI: 10.1097/WNR.0000000000002049 -
Synapse (New York, N.Y.) Jul 2024N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B...
Individual NMDA receptor GluN2 subunit signaling domains differentially regulate the postnatal maturation of hippocampal excitatory synaptic transmission and plasticity but not dendritic morphology.
N-methyl-d-aspartate receptors (NMDARs) at hippocampal excitatory synapses undergo a late postnatal shift in subunit composition, from an initial prevalence of GluN2B subunit incorporation to a later predominance of GluN2A. This GluN2B to GluN2A shift alters NMDAR calcium conductance dynamics and intracellular molecular signaling that are individually regulated by distinct GluN2 signaling domains and temporally align with developmental alterations in dendritic and synaptic plasticity. However, the impacts of individual GluN2B to GluN2A signaling domains on neuronal development remain unknown. Ionotropic and intracellular signaling domains of GluN2 subunits were separated by creating chimeric GluN2 subunits that were expressed in two transgenic mouse lines. Western blot and immunoprecipitation revealed that roughly one third of native synaptic NMDARs were replaced by transformed NMDARs without altering total synaptic NMDAR content. Schaffer collateral synaptic strength was transiently increased in acutely prepared hippocampal slices at just over 3 weeks of age in animals overexpressing the GluN2B carboxy terminus. Long-term potentiation (LTP) induction following lower frequency stimulation was regulated by GluN2 ionotropic signaling domains in an age-dependent manner and LTP maintenance was enhanced by overexpression of the GluN2B CTD in mature animals. After higher frequency stimulation, the induction and maintenance of LTP were increased in young adult animals overexpressing the GluN2B ionotropic signaling domains but reduced in juveniles just over 3 weeks of age. Confocal imaging of green fluorescent protein (GFP)- labeled CA1 pyramidal neurons revealed no alterations in dendritic morphology or spine density in mice expressing chimeric GluN2 subunits. These results illustrate how individual GluN2 subunit signaling domains do or do not control physiological and morphological development of hippocampal excitatory neurons and better clarify the neurobiological factors that govern hippocampal maturation. SIGNIFICANCE STATEMENT: A developmental reduction in the magnitude of hippocampal long-term synaptic potentiation (LTP) and a concomitant improvement in spatial maze performance coincide with greater incorporation of GluN2A subunits into synaptic NMDARs. Corroborating our prior discovery that overexpression of GluN2A-type ionotropic signaling domains enables context-based navigation in immature mice, GluN2A-type ionotropic signaling domain overexpression reduces LTP induction threshold and magnitude in immature mice. Also, we previously found that GluN2B carboxy terminal domain (CTD) overexpression enhances long-term spatial memory in mature mice and now report that the GluN2B CTD is associated with greater amplitude of LTP after induction in mature mice. Thus, the late postnatal maturation of context encoding likely relies on a shift toward GluN2A-type ionotropic signaling and a reduction in the threshold to induce LTP while memory consolidation and LTP maintenance are regulated by GluN2B subunit CTD signaling.
Topics: Animals; Receptors, N-Methyl-D-Aspartate; Hippocampus; Dendrites; Mice, Transgenic; Mice; Neuronal Plasticity; Long-Term Potentiation; Synaptic Transmission; Excitatory Postsynaptic Potentials; Signal Transduction; Mice, Inbred C57BL; Male
PubMed: 38813758
DOI: 10.1002/syn.22292 -
Journal of Neurochemistry May 2024Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by... (Review)
Review
Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl-prolyl cis/trans isomerase, NIMA-Interacting 1 (PIN1) is a peptidyl-prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over-expression is linked to cancer. Death-associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high-level signaling molecules, such as nuclear factor erythroid 2-related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism.
PubMed: 38808598
DOI: 10.1111/jnc.16140 -
Frontiers in Molecular Neuroscience 2024Zinc transporter 3 (ZnT) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In...
Zinc transporter 3 (ZnT) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT knockout mice. We hypothesize that the ZnT deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.
PubMed: 38807922
DOI: 10.3389/fnmol.2024.1375925 -
Neuroscience Bulletin May 2024Alcohol abuse induces various neurological disorders including motor learning deficits, possibly by affecting neuronal and astrocytic activity. Physical exercise is one...
Alcohol abuse induces various neurological disorders including motor learning deficits, possibly by affecting neuronal and astrocytic activity. Physical exercise is one effective approach to remediate synaptic loss and motor deficits as shown by our previous works. In this study, we unrevealed the role of exercise training in the recovery of cortical neuronal and astrocytic functions. Using a chronic alcohol injection mouse model, we found the hyperreactivity of astrocytes along with dendritic spine loss plus lower neuronal activity in the primary motor cortex. Persistent treadmill exercise training, on the other hand, improved neural spine formation and inhibited reactive astrocytes, alleviating motor learning deficits induced by alcohol exposure. These data collectively support the potency of endurance exercise in the rehabilitation of motor functions under alcohol abuse.
PubMed: 38807019
DOI: 10.1007/s12264-024-01226-x -
Scientific Reports May 2024Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate...
Sex hormones affect structural and functional plasticity in the rodent hippocampus. However, hormone levels not only differ between males and females, but also fluctuate across the female estrous cycle. While sex- and cycle-dependent differences in dendritic spine density and morphology have been found in the rodent CA1 region, but not in the CA3 or the dentate gyrus, comparable structural data on CA2, i.e. the hippocampal region involved in social recognition memory, is so far lacking. In this study, we, therefore, used wildtype male and female mice in diestrus or proestrus to analyze spines on dendritic segments from identified CA2 neurons. In basal stratum oriens, we found no differences in spine density, but a significant shift towards larger spine head areas in male mice compared to females. Conversely, in apical stratum radiatum diestrus females had a significantly higher spine density, and females in either cycle stage had a significant shift towards larger spine head areas as compared to males, with diestrus females showing the larger shift. Our results provide further evidence for the sexual dimorphism of hippocampal area CA2, and underscore the importance of considering not only the sex, but also the stage of the estrous cycle when interpreting morphological data.
Topics: Animals; Male; Female; Dendritic Spines; Mice; Estrous Cycle; CA2 Region, Hippocampal; Sex Characteristics; Neurons
PubMed: 38806649
DOI: 10.1038/s41598-024-62951-x -
Scientific Reports May 2024Cranial irradiation used to control brain malignancies invariably leads to progressive and debilitating declines in cognition. Clinical efforts implementing hippocampal...
Cranial irradiation used to control brain malignancies invariably leads to progressive and debilitating declines in cognition. Clinical efforts implementing hippocampal avoidance and NMDAR antagonism, have sought to minimize dose to radiosensitive neurogenic regions while normalizing excitatory/inhibitory (E/I) tone. Results of these trials have yielded only marginal benefits to cognition, prompting current studies to evaluate the potential of systemic extracellular vesicle (EV) therapy to restore neurocognitive functionality in the irradiated brain. Here we tested the hypothesis that EVs derived from inhibitory but not excitatory neuronal cultures would prove beneficial to cognition and associated pathology. Rats subjected to a clinically relevant, fractionated cranial irradiation paradigm were given multiple injections of either GABAergic- or glutamatergic-derived EV and subjected to behavioral testing. Rats treated with GABAergic but not glutamatergic EVs showed significant improvements on hippocampal- and cortical-dependent behavioral tasks. While each treatment enhanced levels of the neurotrophic factors BDNF and GDNF, only GABAergic EVs preserved granule cell neuron dendritic spine density. Additional studies conducted with GABAergic EVs, confirmed significant benefits on amygdala-dependent behavior and modest changes in synaptic plasticity as measured by long-term potentiation. These data point to a potentially more efficacious approach for resolving radiation-induced neurological deficits, possibly through a mechanism able to restore homeostatic E/I balance.
Topics: Animals; Extracellular Vesicles; Rats; Cranial Irradiation; GABAergic Neurons; Male; Hippocampus; Brain-Derived Neurotrophic Factor; Neurons; Glutamic Acid; Neuronal Plasticity; Glial Cell Line-Derived Neurotrophic Factor; Behavior, Animal
PubMed: 38806540
DOI: 10.1038/s41598-024-62691-y -
Frontiers in Cellular Neuroscience 2024Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive...
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive stereotyped behaviors along with variable associated features. , a gene linked to ASD, encodes CUL3 (CULLIN-3), a protein that serves as a key component of a ubiquitin ligase complex with unclear function in neurons. homozygous deletion in mice is embryonic lethal; thus, we examine the role of deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures. Homozygous deletion of significantly decreased dendritic complexity and dendritic length, as well as axon formation. Synaptic spine density significantly increased, mainly in thin and stubby spines along with decreased average spine volume in knockouts. Both heterozygous and homozygous knockout of caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged. Based on previous studies implicating elevated caspase-3 after deletion, we demonstrated increased caspase-3 in our neuronal cultures and decreased neuronal cell viability. We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition. Studies have also implicated caspase-3 in neuronal morphological changes. We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes. Overall, these data provide additional evidence that regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture.
PubMed: 38803442
DOI: 10.3389/fncel.2024.1320784