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International Journal of Molecular... Apr 2021Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry... (Review)
Review
Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.
Topics: Actin Cytoskeleton; Animals; Brain Diseases; Dendritic Spines; Disease Models, Animal; Neuronal Plasticity; Synaptic Transmission
PubMed: 33919977
DOI: 10.3390/ijms22084053 -
Developmental Neurobiology Jul 2021Dendritic spines are membranous protrusions that receive essentially all excitatory inputs in most mammalian neurons. Spines, with a bulbous head connected to the...
Dendritic spines are membranous protrusions that receive essentially all excitatory inputs in most mammalian neurons. Spines, with a bulbous head connected to the dendrite by a thin neck, have a variety of morphologies that likely impact their functional properties. Nevertheless, the question of whether spines belong to distinct morphological subtypes is still open. Addressing this quantitatively requires clear identification and measurements of spine necks. Recent advances in electron microscopy enable large-scale systematic reconstructions of spines with nanometer precision in 3D. Analyzing ultrastructural reconstructions from mouse neocortical neurons with computer vision algorithms, we demonstrate that the vast majority of spine structures can be rigorously separated into heads and necks, enabling morphological measurements of spine necks. We then used a database of spine morphological parameters to explore the potential existence of different spine classes. Without exception, our analysis revealed unimodal distributions of individual morphological parameters of spine heads and necks, without evidence for subtypes of spines. The postsynaptic density size was strongly correlated with the spine head volume. The spine neck diameter, but not the neck length, was also correlated with the head volume. Spines with larger head volumes often had a spine apparatus and pairs of spines in a post-synaptic cell contacted by the same axon had similar head volumes. Our data reveal a lack of morphological subtypes of spines and indicate that the spine neck length and head volume must be independently regulated. These results have repercussions for our understanding of the function of dendritic spines in neuronal circuits.
Topics: Animals; Axons; Dendrites; Dendritic Spines; Mammals; Mice; Microscopy, Electron; Neurons; Synapses
PubMed: 33977655
DOI: 10.1002/dneu.22829 -
The Neuroscientist : a Review Journal... Oct 2021Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such... (Review)
Review
Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles associated with Alzheimer's disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer's disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer's disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer's disease.
Topics: Aging; Alzheimer Disease; Brain; Cognition; Dendritic Spines; Humans
PubMed: 32812494
DOI: 10.1177/1073858420945964 -
Molecular and Cellular Neurosciences Jul 2019EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has...
EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2 or Epac2 mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2 mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.
Topics: Animals; Cadherins; Cells, Cultured; Dendritic Spines; Excitatory Postsynaptic Potentials; Guanine Nucleotide Exchange Factors; Gyrus Cinguli; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Inbred C57BL; Receptors, AMPA; Synapses; Vesicular Inhibitory Amino Acid Transport Proteins
PubMed: 31059774
DOI: 10.1016/j.mcn.2019.05.001 -
ELife Feb 2023Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with...
Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglial motility and significance for synapse stability, especially in the hippocampus during adulthood, remain widely unresolved. Here, we investigated the effect of neuronal activity on microglial motility and the implications for the formation and survival of dendritic spines on hippocampal CA1 neurons in vivo. We used repetitive two-photon in vivo imaging in the hippocampus of awake and anesthetized mice to simultaneously study the motility of microglia and their interaction with dendritic spines. We found that CA3 to CA1 input is sufficient to modulate microglial process motility. Simultaneously, more dendritic spines emerged in mice after awake compared to anesthetized imaging. Interestingly, the rate of microglial contacts with individual dendritic spines and dendrites was associated with the stability, removal, and emergence of dendritic spines. These results suggest that microglia might sense neuronal activity via neurotransmitter release and actively participate in synaptic rewiring of the hippocampal neural network during adulthood. Further, this study has profound relevance for hippocampal learning and memory processes.
Topics: Mice; Animals; Microglia; Dendritic Spines; Wakefulness; Hippocampus; Neurons; Neuronal Plasticity
PubMed: 36749020
DOI: 10.7554/eLife.83176 -
Trends in Neurosciences Jan 2023The heterogeneity of the endoplasmic reticulum (ER) makes it a versatile platform for a broad range of homeostatic processes, ranging from calcium regulation to... (Review)
Review
The heterogeneity of the endoplasmic reticulum (ER) makes it a versatile platform for a broad range of homeostatic processes, ranging from calcium regulation to synthesis and trafficking of proteins and lipids. It is not surprising that neurons use this organelle to fine-tune synaptic properties and thereby provide specificity to synaptic inputs. In this review, we discuss the mechanisms that enable activity-dependent ER recruitment into dendritic spines, with a focus on molecular mechanisms that mediate transport and retention of the ER in spines. The role of calcium signaling in spine ER, synaptopodin 'tagging' of active synapses, and the formation of the spine apparatus (SA) are highlighted. Finally, we discuss the role of liquid-liquid phase separation as a possible driving force in these processes.
Topics: Humans; Hippocampus; Endoplasmic Reticulum; Neurons; Dendritic Spines; Synapses; Calcium
PubMed: 36428191
DOI: 10.1016/j.tins.2022.10.012 -
Developmental Neurobiology Jul 2021Dendritic spines are small dendritic protrusions that harbor most excitatory synapses in the brain. The proper generation and maturation of dendritic spines are crucial... (Review)
Review
Dendritic spines are small dendritic protrusions that harbor most excitatory synapses in the brain. The proper generation and maturation of dendritic spines are crucial for the regulation of synaptic transmission and formation of neuronal circuits. Abnormalities in dendritic spine density and morphology are common pathologies in autism and schizophrenia. According to epidemiological studies, one risk factor for these neurodevelopmental disorders is maternal infection during pregnancy. This review discusses spine alterations in animal models of maternal immune activation in the context of neurodevelopmental disorders. We describe potential mechanisms that might be responsible for prenatal infection-induced changes in the dendritic spine phenotype and behavior in offspring.
Topics: Animals; Autistic Disorder; Dendritic Spines; Female; Neurodevelopmental Disorders; Neurons; Pregnancy; Synapses
PubMed: 33382515
DOI: 10.1002/dneu.22804 -
Neuroscience Research Sep 2022BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2)....
BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.
Topics: Adenosine Triphosphate; Animals; Dendritic Spines; GTP Phosphohydrolases; Mice; Mitochondrial Dynamics; Mitochondrial Proteins; bcl-2-Associated X Protein
PubMed: 35688289
DOI: 10.1016/j.neures.2022.06.002 -
ACS Chemical Neuroscience Jun 2018Therapeutics to effectively treat Alzheimer's disease (AD) are lacking. In vitro, animal and human studies have implicated the excessive activation of the protein... (Review)
Review
Therapeutics to effectively treat Alzheimer's disease (AD) are lacking. In vitro, animal and human studies have implicated the excessive activation of the protein phosphatase calcineurin (CN) as an early step in the pathogenesis of AD. We discuss recent data showing that the prolyl isomerase Pin1 is suppressed by CN-mediated dephosphorylation induced by Aβ42 signaling. Pin1 loss directly leads to the reductions in dendritic spines and synapses characteristic of early AD pathology. Pin1 activity, and synapse and dendritic spine numbers are rescued by FK506, a highly specific and United States Food and Drug Administration approved CN inhibitor. Solid organ transplant recipients chronically treated with FK506 showed much lower AD incidence than expected. As such, we suggest prospective clinical trials to determine if systemic FK506 can normalize CN activity in the brain, preserve Pin1 function and support synaptic health in early AD.
Topics: Alzheimer Disease; Animals; Brain; Calcineurin Inhibitors; Dendritic Spines; Humans; Synapses; Tacrolimus
PubMed: 29757603
DOI: 10.1021/acschemneuro.8b00213 -
Journal of Visualized Experiments : JoVE Dec 2021Golgi impregnation, using the Golgi staining kit with minor adaptations, is used to impregnate dendritic spines in the rat hippocampus and medial prefrontal cortex. This...
Golgi impregnation, using the Golgi staining kit with minor adaptations, is used to impregnate dendritic spines in the rat hippocampus and medial prefrontal cortex. This technique is a marked improvement over previous methods of Golgi impregnation because the premixed chemicals are safer to use, neurons are consistently well impregnated, there is far less background debris, and for a given region, there are extremely small deviations in spine density between experiments. Moreover, brains can be accumulated after a certain point and kept frozen until further processing. Using this method any brain region of interest can be studied. Once stained and cover slipped, dendritic spine density is determined by counting the number of spines for a length of dendrite and expressed as spine density per 10 µm dendrite.
Topics: Animals; Coloring Agents; Dendrites; Dendritic Spines; Hippocampus; Neurons; Prefrontal Cortex; Rats
PubMed: 34927620
DOI: 10.3791/63404