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The Journal of Neuroscience : the... Jun 2024Shank3 is a synaptic scaffolding protein that assists in tethering and organizing structural proteins and glutamatergic receptors in the postsynaptic density of...
Shank3 is a synaptic scaffolding protein that assists in tethering and organizing structural proteins and glutamatergic receptors in the postsynaptic density of excitatory synapses. The localization of Shank3 at excitatory synapses and the formation of stable Shank3 complexes is regulated by the binding of zinc to the C-terminal sterile-alpha-motif (SAM) domain of Shank3. Mutations in the SAM domain of result in altered synaptic function and morphology, and disruption of zinc in synapses that express Shank3 leads to a reduction of postsynaptic proteins important for synaptic structure and function. This suggests that zinc supports the localization of postsynaptic proteins via Shank3. Many regions of the brain are highly enriched with free zinc inside glutamatergic vesicles at presynaptic terminals. At these synapses, zinc transporter 3 (ZnT3) moves zinc into vesicles where it is co-released with glutamate. Alterations in ZnT3 are implicated in multiple neurodevelopmental disorders, and ZnT3 knock-out (KO) mice - which lack synaptic zinc - show behavioral deficits associated with autism spectrum disorder and schizophrenia. Using male and female mice, we show that ZnT3 KO mice have smaller dendritic spines and miniature excitatory postsynaptic current amplitudes than wildtype (WT) mice in the auditory cortex. Additionally, spine size deficits in ZnT3 KO mice are restricted to synapses that express Shank3. In WT mice, synapses that express both Shank3 and ZnT3 have larger spines compared to synapses that express Shank3 but not ZnT3. Together these findings suggest a mechanism whereby presynaptic ZnT3-dependent zinc supports postsynaptic structure and function via Shank3 in a synapse-specific manner. Shank3 is a scaffolding protein that assists in the organization of glutamatergic receptors in the postsynaptic density of excitatory synapses in the brain. The structure and function of Shank3 is regulated by zinc ions. Specifically, zinc allows Shank3 to form tight sheets that assist in stabilizing the postsynaptic density. Zinc packaged by the zinc transporter ZnT3 which is released from presynaptic terminals may contribute to the function of Shank3. In this study, we find an association between ZnT3, Shank3, synaptic strength, and spine size, suggesting that zinc released from presynaptic terminals supports dendritic spine structure and function via interactions with Shank3.
PubMed: 38830758
DOI: 10.1523/JNEUROSCI.0619-24.2024 -
Neurologia Jun 2024Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex,...
Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias.
Topics: Animals; Purkinje Cells; Male; Rats, Sprague-Dawley; Rats; Cerebellum; Cerebellar Ataxia; Pyridines; Neuronal Plasticity
PubMed: 38830720
DOI: 10.1016/j.nrleng.2021.09.015 -
Alzheimer's & Dementia : the Journal of... Jun 2024Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting Alzheimer's disease (AD) histopathological...
INTRODUCTION
Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting Alzheimer's disease (AD) histopathological signs. Investigating the mechanisms behind this resilience may unveil crucial insights into AD resistance.
METHODS
DiI labeling technique was used to analyze dendritic spine morphology in control (CTRL), AD, and NDAN post mortem frontal cortex, particularly focusing on spine types near and far from amyloid beta (Aβ) plaques.
RESULTS
NDAN subjects displayed a higher spine density in regions distant from Aβ plaques versus AD patients. In distal areas from the plaques, NDAN individuals exhibited more immature spines, while AD patients had a prevalence of mature spines. Additionally, our examination of levels of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), a protein associated with synaptic plasticity and AD, showed significantly lower expression in AD versus NDAN and CTRL.
DISCUSSION
These results suggest that NDAN individuals undergo synaptic remodeling, potentially facilitated by Pin1, serving as a compensatory mechanism to preserve cognitive function despite AD pathology.
HIGHLIGHTS
Spine density is reduced near Aβ plaques compared to the distal area in CTRL, AD, and NDAN dendrites. NDAN shows higher spine density than AD in areas far from Aβ plaques. Far from Aβ plaques, NDAN has a higher density of immature spines, AD a higher density of mature spines. AD individuals show significantly lower levels of Pin1 compared to NDAN and CTRL.
PubMed: 38829680
DOI: 10.1002/alz.13900 -
Molecular Neurobiology Jun 2024CELF2 variants have been linked to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, the molecular mechanisms remain unclear. We...
CELF2 variants have been linked to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, the molecular mechanisms remain unclear. We generated Celf2 Nestin-Cre knockout mice.Our findings revealed that Celf2 Nestin-Cre heterozygous knockout mice exhibited social impairment and anxiety, an autism-like behavior, though no manifestations of repetitive stereotyped behavior, learning cognitive impairment, or depression were observed. Immunofluorescence assay showed an underdeveloped cerebral cortex with significantly reduced cortical thickness, albeit without abnormal cell density. Further in vitro neuronal culture demonstrated a significant reduction in dendritic spine density and affected synaptic maturation in Celf2 deficient mice, with no notable abnormalities in total neurite and axon length. RNA-seq and RIP-seq analysis of the cerebral cortex revealed differentially expressed genes post Celf2 gene knockout compared with the control group. Enrichment analysis highlighted significant enrichment in dendrite and synapse-related biological processes and pathways. Our study delineated the behavioral and neurodevelopmental phenotypes of Celf2, suggesting its potential involvement in autism through the regulation of target genes associated with dendritic spines and synapse development. Further research is needed to elucidate the specific mechanisms involved.
PubMed: 38829512
DOI: 10.1007/s12035-024-04250-0 -
BioRxiv : the Preprint Server For... May 2024How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity...
How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to pre-plasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels.
PubMed: 38826343
DOI: 10.1101/2024.05.24.595787 -
Journal of Affective Disorders May 2024Accumulative evidence suggested that the oxytocin system plays a role in socio-emotional disorders, although its role in neuroinflammation-induced anxiety remains...
BACKGROUND
Accumulative evidence suggested that the oxytocin system plays a role in socio-emotional disorders, although its role in neuroinflammation-induced anxiety remains unclear.
METHOD
In the present study, anxiety-like behavior was induced in cohorts of animals through repeated lipopolysaccharide (LPS, 0.5 mg/kg, daily, Escherichia coli O55:B5) i.p. injections for seven consecutive days. These different cohorts were subsequently used for anxiety-like behavior assessment with open field test, elevated plus maze, and novelty-suppressed feeding test or for electrophysiology (EEG) recordings of miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs), or local field potential (LFP) in vivo or ex vivo settings. Samples of the anterior cingulate cortex (ACC) from some cohorts were harvested to conduct immunostaining or western blotting analysis of oxytocin, oxytocin receptor, CamkII, GABA, vGAT, vGLUT2, and c-fos. The dendritic spine density was assessed by Golgi-Cox staining.
RESULTS
Repeated LPS injections induced anxiety-like behavior with concurrent decreases of oxytocin, vGLUT2, mEPSC, dendritic spine, c-fos, membrane excitability, and EEG beta and gamma oscillations, but increased oxytocin receptor and vGAT expressions in the ACC; all these changes were ameliorated by oxytocin intranasal or local brain (via cannula) administration.
CONCLUSION
Taken together, our data suggested that oxytocin system may be a therapeutic target for developing treatment to tackle neuroinflammation-induced anxiety.
PubMed: 38821372
DOI: 10.1016/j.jad.2024.05.144 -
Progress in Neurobiology Jul 2024Habits are familiar behaviors triggered by cues, not outcome predictability, and are insensitive to changes in the environment. They are adaptive under many...
Habits are familiar behaviors triggered by cues, not outcome predictability, and are insensitive to changes in the environment. They are adaptive under many circumstances but can be considered antecedent to compulsions and intrusive thoughts that drive persistent, potentially maladaptive behavior. Whether compulsive-like and habit-like behaviors share neural substrates is still being determined. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice demonstrate habitual response biases and compulsive-like grooming behavior that was reversible by fluoxetine and ketamine. They also suffer dendritic spine attrition on excitatory neurons in the orbitofrontal cortex (OFC). Nevertheless, synaptic melanocortin 4 receptor (MC4R), a factor implicated in compulsive behavior, is preserved, leading to the hypothesis that Mc4r+ OFC neurons may drive aberrant behaviors. Repeated chemogenetic stimulation of Mc4r+ OFC neurons triggered compulsive and not inflexible or habitual response biases in otherwise typical mice. Thus, Mc4r+ neurons within the OFC appear to drive compulsive-like behavior that is dissociable from habitual behavior. Understanding which neuron populations trigger distinct behaviors may advance efforts to mitigate harmful compulsions.
Topics: Animals; Compulsive Behavior; Mice; Neurons; Prefrontal Cortex; Habits; Choice Behavior; Receptor, Melanocortin, Type 4; Male; Reward; Behavior, Animal; Grooming; Mice, Transgenic; Dendritic Spines; Female
PubMed: 38821345
DOI: 10.1016/j.pneurobio.2024.102632 -
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