ABSTRACT
This article comprehensively reviews how cerebral hypoxia impacts the physiological state of neurons and dendritic spines through a series of molecular changes, and explores the causal relationship between these changes and neuronal functional impairment. As a severe pathological condition, cerebral hypoxia can significantly alter the morphology and function of neurons and dendritic spines. Specifically, dendritic spines, being the critical structures for neurons to receive information, undergo changes such as a reduction in number and morphological abnormalities under hypoxic conditions. These alterations further affect synaptic function, leading to neurotransmission disorders. This article delves into the roles of molecular pathways like MAPK, AMPA receptors, NMDA receptors, and BDNF in the hypoxia-induced changes in neurons and dendritic spines, and outlines current treatment strategies. Neurons are particularly sensitive to cerebral hypoxia, with their apical dendrites being vulnerable to damage, thereby affecting cognitive function. Additionally, astrocytes and microglia play an indispensable role in protecting neuronal and synaptic structures, regulating their normal functions, and contributing to the repair process following injury. These studies not only contribute to understanding the pathogenesis of related neurological diseases but also provide important insights for developing novel therapeutic strategies. Future research should further focus on the dynamic changes in neurons and dendritic spines under hypoxic conditions and their intrinsic connections with cognitive function.
Subject(s)
Dendritic Spines , Neurons , Dendritic Spines/metabolism , Dendritic Spines/pathology , Animals , Humans , Neurons/metabolism , Neurons/pathology , Hypoxia, Brain/pathology , Hypoxia, Brain/metabolism , Hypoxia, Brain/physiopathologyABSTRACT
Synaptic dysfunction is an early pathogenic event leading to cognitive decline in Huntington's disease (HD). We previously reported that the active ADAM10 level is increased in the HD cortex and striatum, causing excessive proteolysis of the synaptic cell adhesion protein N-Cadherin. Conversely, ADAM10 inhibition is neuroprotective and prevents cognitive decline in HD mice. Although the breakdown of cortico-striatal connection has been historically linked to cognitive deterioration in HD, dendritic spine loss and long-term potentiation (LTP) defects identified in the HD hippocampus are also thought to contribute to the cognitive symptoms of the disease. The aim of this study is to investigate the contribution of ADAM10 to spine pathology and LTP defects of the HD hippocampus. We provide evidence that active ADAM10 is increased in the hippocampus of two mouse models of HD, leading to extensive proteolysis of N-Cadherin, which has a widely recognized role in spine morphology and synaptic plasticity. Importantly, the conditional heterozygous deletion of ADAM10 in the forebrain of HD mice resulted in the recovery of spine loss and ultrastructural synaptic defects in CA1 pyramidal neurons. Meanwhile, normalization of the active ADAM10 level increased the pool of synaptic BDNF protein and activated ERK neuroprotective signaling in the HD hippocampus. We also show that the ADAM10 inhibitor GI254023X restored LTP defects and increased the density of mushroom spines enriched with GluA1-AMPA receptors in HD hippocampal neurons. Notably, we report that administration of the TrkB antagonist ANA12 to HD hippocampal neurons reduced the beneficial effect of GI254023X, indicating that the BDNF receptor TrkB contributes to mediate the neuroprotective activity exerted by ADAM10 inhibition in HD. Collectively, these findings indicate that ADAM10 inhibition coupled with TrkB signaling represents an efficacious strategy to prevent hippocampal synaptic plasticity defects and cognitive dysfunction in HD.
Subject(s)
ADAM10 Protein , Amyloid Precursor Protein Secretases , Hippocampus , Huntington Disease , Long-Term Potentiation , Membrane Proteins , Receptor, trkB , Signal Transduction , Animals , ADAM10 Protein/metabolism , ADAM10 Protein/genetics , Huntington Disease/metabolism , Huntington Disease/pathology , Mice , Amyloid Precursor Protein Secretases/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Hippocampus/metabolism , Hippocampus/pathology , Receptor, trkB/metabolism , Receptor, trkB/antagonists & inhibitors , Long-Term Potentiation/drug effects , Membrane Proteins/metabolism , Membrane Proteins/genetics , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Cadherins/metabolism , Dendritic Spines/metabolism , Dendritic Spines/pathology , Neuroprotection , Male , Mice, Inbred C57BL , Neuronal Plasticity , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Mice, KnockoutABSTRACT
BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.
Subject(s)
Circadian Rhythm , Dendritic Spines , Fasting , Animals , Fasting/physiology , Mice , Circadian Rhythm/physiology , Dendritic Spines/pathology , Male , Brain Ischemia/pathology , Brain Ischemia/physiopathology , Mice, Inbred C57BL , Recovery of Function/physiology , Intermittent FastingABSTRACT
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 (Aß) plaques. RESULTS: NDAN subjects displayed a higher spine density in regions distant from Aß 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 Aß plaques compared to the distal area in CTRL, AD, and NDAN dendrites. NDAN shows higher spine density than AD in areas far from Aß plaques. Far from Aß 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.
Subject(s)
Alzheimer Disease , Dendritic Spines , Humans , Dendritic Spines/pathology , Alzheimer Disease/pathology , Male , Female , Aged , Aged, 80 and over , Plaque, Amyloid/pathology , Neuronal Plasticity/physiology , Cognition/physiology , Frontal Lobe/pathologyABSTRACT
Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced susceptibility to anxiety disorders remain elusive. The lateral septum (LS), primarily composed of γ-aminobutyric acidergic (GABAergic) neurons, serves as a key brain region in the regulation of anxiety. However, it remains unclear whether LS GABAergic neurons are implicated in propofol-induced anxiety. Therefore, we conducted c-Fos immunostaining of whole-brain slices from mice exposed to propofol during early life. Our findings indicate that propofol exposure activates GABAergic neurons in the LS. Selective activation of LS GABAergic neurons resulted in increased anxiety-like behavior, while selective inhibition of these neurons reduced such behaviors. These results suggest that the LS is a critical brain region involved in propofol-induced anxiety. Furthermore, we investigated the molecular mechanism of propofol-induced anxiety in the LS. Microglia activation underlies the development of anxiety. Immunofluorescence staining and Western blot analysis of LS revealed activated microglia and significantly elevated levels of phospho-NF-κB p65 protein. Additionally, a decrease in the number of neuronal spines was observed. Our study highlights the crucial role of the LS in the development of anxiety-like behavior in adulthood following childhood propofol exposure, accompanied by the activation of inflammatory pathways.
Subject(s)
Anxiety , Behavior, Animal , GABAergic Neurons , Microglia , Propofol , Propofol/pharmacology , Animals , Anxiety/chemically induced , Mice , Male , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , GABAergic Neurons/pathology , Behavior, Animal/drug effects , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Proto-Oncogene Proteins c-fos/metabolism , Mice, Inbred C57BL , Transcription Factor RelA/metabolism , Dendritic Spines/drug effects , Dendritic Spines/pathology , Dendritic Spines/metabolismABSTRACT
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.
Subject(s)
Dendritic Spines , Frontotemporal Dementia , Mutation , Protein Isoforms , tau Proteins , tau Proteins/metabolism , tau Proteins/genetics , Animals , Frontotemporal Dementia/genetics , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Dendritic Spines/metabolism , Dendritic Spines/pathology , Rats , Male , Humans , Female , Protein Isoforms/genetics , Protein Isoforms/metabolism , Synapses/metabolism , Synapses/pathology , Rats, Sprague-Dawley , Hippocampus/metabolism , Hippocampus/pathology , Cells, CulturedABSTRACT
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.
Subject(s)
Behavior, Animal , Dendritic Spines , Methyl-CpG-Binding Protein 2 , Phenotype , Receptor, trkB , Rett Syndrome , Animals , Rett Syndrome/pathology , Rett Syndrome/drug therapy , Dendritic Spines/drug effects , Dendritic Spines/metabolism , Dendritic Spines/pathology , Female , Receptor, trkB/metabolism , Methyl-CpG-Binding Protein 2/metabolism , Methyl-CpG-Binding Protein 2/genetics , Behavior, Animal/drug effects , Ligands , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Mice , Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/pathology , Hippocampus/metabolism , Hippocampus/drug effects , Heterozygote , Mice, Inbred C57BL , Disease Models, Animal , BenzamidesABSTRACT
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 cisplatinâ +â 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 (Pâ <â 0.05). These deficits were prevented by the coadministration of melatonin (Pâ <â 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (Pâ <â 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (Pâ <â 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.
Subject(s)
Cisplatin , Dendritic Spines , Hippocampus , Melatonin , Animals , Melatonin/pharmacology , Cisplatin/toxicity , Dendritic Spines/drug effects , Dendritic Spines/pathology , Male , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/metabolism , Rats , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/pathology , Antineoplastic Agents/toxicity , Neuroprotective Agents/pharmacology , Antioxidants/pharmacology , Rats, Wistar , Chemotherapy-Related Cognitive Impairment , Memory, Short-Term/drug effectsABSTRACT
Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.
Subject(s)
Mice, Inbred C57BL , Neuralgia , PPAR alpha , Spinal Cord , Animals , PPAR alpha/metabolism , Neuralgia/drug therapy , Neuralgia/metabolism , Male , Mice , Spinal Cord/metabolism , Spinal Cord/drug effects , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Metabolomics , Microglia/drug effects , Microglia/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Dendritic Spines/drug effects , Dendritic Spines/metabolism , Dendritic Spines/pathology , Inflammasomes/metabolism , Inflammasomes/drug effectsABSTRACT
Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target.
Subject(s)
Callithrix , Disease Models, Animal , Neuronal Plasticity , Oxytocin , Animals , Oxytocin/metabolism , Male , Synapses/metabolism , Dendritic Spines/metabolism , Dendritic Spines/pathology , Dendritic Spines/drug effects , Autism Spectrum Disorder/metabolism , Autistic Disorder/metabolism , Autistic Disorder/pathology , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Prefrontal Cortex/drug effects , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Valproic Acid/pharmacology , Presynaptic Terminals/metabolism , Female , Axons/metabolismABSTRACT
INTRODUCTION: The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions. However, how afferent neurons of mPFC are affected by chronic stress needs to be clarified. In this study, the effects of chronic restraint stress (CRS) on the distribution density of mPFC dendrites/dendritic spines and the projections from the cortex and subcortical brain regions to the mPFC were investigated. METHODS: In the present study, C57BL/6â¯J transgenic (Thy1-YFP-H) mice were subjected to CRS to establish an animal model of depression. The infralimbic (IL) of mPFC was selected as the injection site of retrograde AAV using stereotactic technique. The effects of CRS on dendrites/dendritic spines and afferent neurons of the mPFC IL were investigaed by quantitatively assessing the distribution density of green fluorescent (YFP) positive dendrites/dendritic spines and red fluorescent (retrograde AAV recombinant protein) positive neurons, respectively. RESULTS: The results revealed that retrograde tracing virus labeled neurons were widely distributed in ipsilateral and contralateral cingulate cortex (Cg1), second cingulate cortex (Cg2), prelimbic cortex (PrL), infralimbic cortex, medial orbital cortex (MO), and dorsal peduncular cortex (DP). The effects of CRS on the distribution density of mPFC red fluorescence positive neurons exhibited regional differences, ranging from rostral to caudal or from top to bottom. Simultaneously, CRS resulted a decrease in the distribution density of basal, proximal and distal dendrites, as well as an increase in the loss of dendritic spines of the distal dendrites in the IL of mPFC. Furthermore, varying degrees of red retrograde tracing virus fluorescence signals were observed in other cortices, amygdala, hippocampus, septum/basal forebrain, hypothalamus, thalamus, mesencephalon, and brainstem in both ipsilateral and contralateral brain. CRS significantly reduced the distribution density of red fluorescence positive neurons in other cortices, hippocampus, septum/basal forebrain, hypothalamus, and thalamus. Conversely, CRS significantly increased the distribution density of red fluorescence positive neurons in amygdala. CONCLUSION: Our results suggest a possible mechanism that CRS leads to disturbances in synaptic plasticity by affecting multiple inputs to the mPFC, which is characterized by a decrease in the distribution density of dendrites/dendritic spines in the IL of mPFC and a reduction in input neurons of multiple cortices to the IL of mPFC as well as an increase in input neurons of amygdala to the IL of mPFC, ultimately causing depression-like behaviors.
Subject(s)
Depression , Mice, Inbred C57BL , Mice, Transgenic , Prefrontal Cortex , Restraint, Physical , Stress, Psychological , Animals , Prefrontal Cortex/pathology , Prefrontal Cortex/metabolism , Stress, Psychological/pathology , Stress, Psychological/metabolism , Mice , Depression/pathology , Male , Dendritic Spines/pathology , Disease Models, Animal , Afferent Pathways , Dendrites/pathology , Dendrites/metabolism , Neurons, Afferent/pathology , Neurons, Afferent/metabolism , Brain/pathology , Brain/metabolismABSTRACT
Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02âM V2O5 1âh, 3/week for 6 months) groups (nâ=â10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.
Subject(s)
Alzheimer Disease , Brain , Disease Models, Animal , Spatial Memory , Vanadium Compounds , Animals , Male , Administration, Inhalation , Alzheimer Disease/chemically induced , Alzheimer Disease/pathology , Amygdala/drug effects , Amygdala/pathology , Brain/drug effects , Brain/pathology , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/pathology , Cerebral Amyloid Angiopathy/chemically induced , Cerebral Amyloid Angiopathy/pathology , Dendritic Spines/drug effects , Dendritic Spines/pathology , Entorhinal Cortex/drug effects , Entorhinal Cortex/pathology , Frontal Lobe/drug effects , Frontal Lobe/pathology , Maze Learning/drug effects , Neurofibrillary Tangles/drug effects , Neurofibrillary Tangles/pathology , Plaque, Amyloid/chemically induced , Plaque, Amyloid/pathology , Rats, Wistar , Spatial Memory/drug effects , Vanadium Compounds/administration & dosage , Vanadium Compounds/toxicityABSTRACT
Since Cajal introduced dendritic spines in the 19th century, they have attained considerable attention, especially in neuropsychiatric and neurologic disorders. Multiple roles of dendritic spine malfunction and pathology in the progression of various diseases have been reported. Thus, it is inevitable to consider these structures as new therapeutic targets for treating neuropsychiatric and neurologic disorders such as autism spectrum disorders, schizophrenia, dementia, Down syndrome, etc. Therefore, we attempted to prepare a narrative review of the literature regarding the role of dendritic spines in the pathogenesis of aforementioned diseases and to shed new light on their pathophysiology.
Subject(s)
Dendritic Spines , Nervous System Diseases , Neurodevelopmental Disorders , Humans , Dendritic Spines/pathology , Nervous System Diseases/physiopathology , Nervous System Diseases/pathology , Nervous System Diseases/etiology , Animals , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/physiopathologyABSTRACT
Synapses are lost on a massive scale in the brain and spinal cord of people living with multiple sclerosis (PwMS), and this synaptic loss extends far beyond demyelinating lesions. Post-mortem studies show the long-term consequences of multiple sclerosis (MS) on synapses but do not inform on the early impacts of neuroinflammation on synapses that subsequently lead to synapse loss. How excitatory circuit inputs are altered across the dendritic tree of individual neurons under neuroinflammatory stress is not well understood. Here, we directly assessed the structural dynamics of labeled excitatory synapses in experimental autoimmune encephalomyelitis (EAE) as a model of immune-mediated cortical neuronal damage. We used in vivo two-photon imaging and a synthetic tissue-hydrogel super-resolution imaging technique to reveal the dynamics of excitatory synapses, map their location across the dendritic tree of individual neurons, and examine neurons at super-resolution for synaptic loss. We found that excitatory synapses are destabilized but not lost from dendritic spines in EAE, starting with the earliest imaging session before symptom onset. This led to changes in excitatory circuit inputs to individual cells. In EAE, stable synapses are replaced by synapses that appear or disappear across the imaging sessions or repeatedly change at the same location. These unstable excitatory inputs occur closer to one another in EAE than in healthy controls and are distributed across the dendritic tree. When imaged at super-resolution, we found that a small proportion of dendritic protrusions lost their presynapse and/or postsynapse. Our finding of diffuse destabilizing effects of neuroinflammation on excitatory synapses across cortical neurons may have significant functional consequences since normal dendritic spine dynamics and clustering are essential for learning and memory.
Subject(s)
Dendritic Spines , Encephalomyelitis, Autoimmune, Experimental , Neurons , Synapses , Animals , Synapses/pathology , Neurons/metabolism , Mice , Female , Dendritic Spines/pathology , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Cerebral Cortex/physiopathology , Cerebral Cortex/pathology , Spinal Cord/pathologyABSTRACT
Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes underlying Ube3a-dependent ASD remain unclear. Using both male and female mice, we find that neurons in the somatosensory cortex of the Ube3a 2× Tg ASD mouse model display reduced dendritic spine density and increased immature filopodia density. Importantly, the increased gene dosage of Ube3a in astrocytes alone is sufficient to confer alterations in neurons as immature dendritic protrusions, as observed in primary hippocampal neuron cultures. We show that Ube3a overexpression in astrocytes leads to a loss of astrocyte-derived spinogenic protein, thrombospondin-2 (TSP2), due to a suppression of TSP2 gene transcription. By neonatal intraventricular injection of astrocyte-specific virus, we demonstrate that Ube3a overexpression in astrocytes in vivo results in a reduction in dendritic spine maturation in prelimbic cortical neurons, accompanied with autistic-like behaviors in mice. These findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels. SIGNIFICANCE STATEMENT: Increased gene dosage of Ube3a is tied to autism spectrum disorders (ASDs), yet cellular and molecular alterations underlying autistic phenotypes remain unclear. We show that Ube3a overexpression leads to impaired dendritic spine maturation, resulting in reduced spine density and increased filopodia density. We find that dysregulation of spine development is not neuron autonomous, rather, it is mediated by an astrocytic mechanism. Increased gene dosage of Ube3a in astrocytes leads to reduced production of the spinogenic glycoprotein thrombospondin-2 (TSP2), leading to abnormalities in spines. Astrocyte-specific Ube3a overexpression in the brain in vivo confers dysregulated spine maturation concomitant with autistic-like behaviors in mice. These findings indicate the importance of astrocytes in aberrant neurodevelopment and brain function in Ube3a-depdendent ASD.
Subject(s)
Autism Spectrum Disorder , Dendritic Spines , Neuroglia , Ubiquitin-Protein Ligases , Animals , Mice , Astrocytes/metabolism , Astrocytes/pathology , Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/pathology , Cells, Cultured , Dendritic Spines/pathology , Dendritic Spines/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Mice, Inbred C57BL , Mice, Transgenic , Neurogenesis/physiology , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , Neurons/pathology , Somatosensory Cortex/metabolism , Somatosensory Cortex/pathology , Thrombospondins/metabolism , Thrombospondins/genetics , Thrombospondins/biosynthesis , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Alzheimer's disease is neurodegenerative and characterized by progressive cognitive impairment. Synaptic dysfunction appears in the early stage of Alzheimer's disease and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here, we found the transcription factor Maf1 to be upregulated in Alzheimer's disease and determined that conditional knockout of Maf1 in a transgenic mouse model of Alzheimer's disease restored learning and memory function; the downregulation of Maf1 reduced the intraneuronal calcium concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulated the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodelling in neurons. Our results clarify the important role and mechanism of the Maf1-NMDAR1 signalling pathway in stabilizing synaptic structure, neuronal function and behaviour during Alzheimer's disease pathogenesis. This therefore serves as a potential diagnostic and therapeutic target for the early stage of Alzheimer's disease.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Mice, Transgenic , Aged , Animals , Female , Humans , Male , Mice , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Dendritic Spines/metabolism , Dendritic Spines/pathology , Disease Models, Animal , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.
Subject(s)
Autism Spectrum Disorder , Depressive Disorder, Major , Animals , Humans , Dendritic Spines/pathology , Autism Spectrum Disorder/pathology , Depressive Disorder, Major/pathology , Brain/pathology , Synaptic Transmission , Neuronal Plasticity/physiology , Synapses/pathologyABSTRACT
Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.
Subject(s)
Huntington Disease , Mice , Animals , Huntington Disease/genetics , Neuronal Plasticity/physiology , Neurons/pathology , Hippocampus/pathology , Synapses/pathology , Lysosomes/pathology , Dendrites/pathology , Dendritic Spines/pathologyABSTRACT
Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.
Subject(s)
MAP Kinase Kinase Kinases , Tauopathies , Animals , Humans , Mice , Brain/pathology , Cells, Cultured , Dendritic Spines/pathology , Lipopolysaccharides , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , Mice, Knockout , Microglia/metabolism , Neuroinflammatory Diseases/pathology , Sequence Analysis, RNA , Single-Cell Analysis , tau Proteins/genetics , tau Proteins/metabolism , Tauopathies/metabolism , Tauopathies/pathology , Tauopathies/physiopathologyABSTRACT
In males, chronic stress enhances dendritic complexity in the amygdala, a region important in emotion regulation. An amygdalar subregion, the basolateral amygdala (BLA), is influenced by the hippocampus and prefrontal cortex to coordinate emotional learning and memory. This study quantified changes in dendritic complexity of BLA stellate neurons ten days after an unpredictable chronic stressor ended in both male and female rats. In addition, dendritic complexity of hippocampal neurons in male rats was assessed at a similar timepoint. Following Golgi processing, stressed male and female rats showed enhanced BLA dendritic complexity; increased arborization occurred near the soma in males and distally in females. As the brain was sampled ten days after chronic stress ended, BLA dendritic hypertrophy persisted in both sexes after the stressor had ended. For the hippocampus, CA3 dendritic complexity was similar for control and stressed males when assessed eight days after stress ended, suggesting that any stress-induced changes had resolved. These results show persistent enhancement of BLA dendritic arborization in both sexes following chronic stress, reveal sex differences in how BLA hypertrophy manifests, and suggest a putative neurobiological substrate by which chronic stress may create a vulnerable phenotype for emotional dysfunction.