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Neuron Aug 2021Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the...
Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.
Topics: Animals; Cerebral Cortex; Dendrites; Dendritic Spines; Female; Frontal Lobe; Male; Mice; Neuronal Plasticity; Psilocybin; Pyramidal Cells; Synaptic Transmission
PubMed: 34228959
DOI: 10.1016/j.neuron.2021.06.008 -
Neural Plasticity 2016Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated... (Review)
Review
Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms.
Topics: Animals; Brain; Dendritic Spines; Depressive Disorder; Disease Models, Animal; Female; Humans; Male; Mice; Neuronal Plasticity; Rats; Restraint, Physical; Stress, Psychological
PubMed: 26881133
DOI: 10.1155/2016/8056370 -
The Journal of Physiology Mar 2017Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently... (Review)
Review
Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.
Topics: Animals; Astrocytes; Dendritic Spines; Humans; Nervous System Diseases; Neurodevelopmental Disorders; Synapses
PubMed: 27381164
DOI: 10.1113/JP270988 -
The Journal of Neuroscience : the... Oct 2023The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic... (Review)
Review
The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic loss in AD, how neurons compensate for this loss and whether this provides cognitive benefits remain almost completely unexplored. In this review, we describe two potential compensatory mechanisms implemented following synaptic loss: the enlargement of the surviving neighboring synapses and the regeneration of synapses. Because dendritic spines, the postsynaptic site of excitatory synapses, are easily visualized using light microscopy, we focus on a range of microscopy approaches to monitor synaptic loss and compensation. Here, we stress the importance of longitudinal dendritic spine imaging, as opposed to fixed-tissue imaging, to gain insights into the temporal dynamics of dendritic spine compensation. We believe that understanding the molecular mechanisms behind these and other forms of synaptic compensation and regeneration will be critical for the development of therapeutics aiming at delaying the onset of cognitive deficits in AD.
Topics: Humans; Alzheimer Disease; Synapses; Neuronal Plasticity; Cognition Disorders; Neurons; Dendritic Spines
PubMed: 37821232
DOI: 10.1523/JNEUROSCI.0379-23.2023 -
Movement Disorders : Official Journal... Jul 2018Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate-putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia-like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa-induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa-induced complications such as levodopa-induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N-methyl-D-aspartate receptor antagonists, alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa-induced complications in PD. © 2017 International Parkinson and Movement Disorder Society.
Topics: Animals; Antiparkinson Agents; Caudate Nucleus; Dendritic Spines; Dopaminergic Neurons; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Putamen
PubMed: 28880414
DOI: 10.1002/mds.27172 -
The Neuroscientist : a Review Journal... Feb 2019Dynamic modification of synaptic connectivity in response to sensory experience is a vital step in the refinement of brain circuits as they are established during... (Review)
Review
Dynamic modification of synaptic connectivity in response to sensory experience is a vital step in the refinement of brain circuits as they are established during development and modified during learning. In addition to the well-established role for new spine growth and stabilization in the experience-dependent plasticity of neural circuits, dendritic spine elimination has been linked to improvements in learning, and dysregulation of spine elimination has been associated with intellectual disability and behavioral impairment. Proper brain function requires a tightly regulated balance between spine formation and spine elimination. Although most studies have focused on the mechanisms of spine formation, considerable progress has been made recently in delineating the neural activity patterns and downstream molecular mechanisms that drive dendritic spine elimination. Here, we review the current state of knowledge concerning the signaling pathways that drive dendritic spine shrinkage and elimination in the cerebral cortex and we discuss their implication in neuropsychiatric and neurodegenerative disease.
Topics: Animals; Cerebral Cortex; Dendritic Spines; Humans; Learning; Long-Term Synaptic Depression; Mental Disorders; Neurodegenerative Diseases; Neuroglia; Signal Transduction; Synapses
PubMed: 29716431
DOI: 10.1177/1073858418769644 -
Developmental Biology Aug 2022The morphogenesis and plasticity of dendritic spines are associated with synaptic strength, learning, and memory. Dendritic spines are highly compartmentalized... (Review)
Review
The morphogenesis and plasticity of dendritic spines are associated with synaptic strength, learning, and memory. Dendritic spines are highly compartmentalized structures, which makes proteins involved in cellular polarization and membrane compartmentalization likely candidates regulating their formation and maintenance. Indeed, recent studies suggest polarity proteins help form and maintain dendritic spines by compartmentalizing the spine neck and head. Here, we review emerging evidence that polarity proteins regulate dendritic spine plasticity and stability through the cytoskeleton, scaffolding molecules, and signaling molecules. We specifically analyze various polarity complexes known to contribute to different forms of cell polarization processes and examine the essential conceptual context linking these groups of polarity proteins to dendritic spine morphogenesis, plasticity, and cognitive functions.
Topics: Cytoskeleton; Dendritic Spines; Morphogenesis; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 35580729
DOI: 10.1016/j.ydbio.2022.05.007 -
Neuron Sep 2017Since Cajal's first drawings of Golgi stained neurons, generations of researchers have been fascinated by the small protrusions, termed spines, studding many neuronal... (Review)
Review
Since Cajal's first drawings of Golgi stained neurons, generations of researchers have been fascinated by the small protrusions, termed spines, studding many neuronal dendrites. Most excitatory synapses in the mammalian CNS are located on dendritic spines, making spines convenient proxies for excitatory synaptic presence. When in vivo imaging revealed that dendritic spines are dynamic structures, their addition and elimination were interpreted as excitatory synapse gain and loss, respectively. Spine imaging has since become a popular assay for excitatory circuit remodeling. In this review, we re-evaluate the validity of using spine dynamics as a straightforward reflection of circuit rewiring. Recent studies tracking both spines and synaptic markers in vivo reveal that 20% of spines lack PSD-95 and are short lived. Although they account for most spine dynamics, their remodeling is unlikely to impact long-term network structure. We discuss distinct roles that spine dynamics can play in circuit remodeling depending on synaptic content.
Topics: Animals; Dendritic Spines; Nerve Tissue Proteins; Synapses
PubMed: 28957675
DOI: 10.1016/j.neuron.2017.08.008 -
Neuroscience Letters Aug 2015Schizophrenia is a chronic illness affecting approximately 0.5-1% of the world's population. The etiology of schizophrenia is complex, including multiple genes, and... (Review)
Review
Schizophrenia is a chronic illness affecting approximately 0.5-1% of the world's population. The etiology of schizophrenia is complex, including multiple genes, and contributing environmental effects that adversely impact neurodevelopment. Nevertheless, a final common result, present in many subjects with schizophrenia, is impairment of pyramidal neuron dendritic morphology in multiple regions of the cerebral cortex. In this review, we summarize the evidence of reduced dendritic spine density and other dendritic abnormalities in schizophrenia, evaluate current data that informs the neurodevelopment timing of these impairments, and discuss what is known about possible upstream sources of dendritic spine loss in this illness.
Topics: Age Factors; Animals; Brain; Dendritic Spines; Humans; Schizophrenia
PubMed: 25478958
DOI: 10.1016/j.neulet.2014.11.042 -
Brain Structure & Function Sep 2021Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions... (Review)
Review
Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.
Topics: Actin Cytoskeleton; Anesthesia, General; Anesthetics, General; Dendritic Spines; Neuronal Plasticity
PubMed: 34061250
DOI: 10.1007/s00429-021-02308-6