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Neuron Jan 2024The pathophysiology of affective disorders-particularly circuit-level mechanisms underlying bidirectional, periodic affective state transitions-remains poorly...
The pathophysiology of affective disorders-particularly circuit-level mechanisms underlying bidirectional, periodic affective state transitions-remains poorly understood. In patients, disruptions of sleep and circadian rhythm can trigger transitions to manic episodes, whereas depressive states are reversed. Here, we introduce a hybrid automated sleep deprivation platform to induce transitions of affective states in mice. Acute sleep loss causes mixed behavioral states, featuring hyperactivity, elevated social and sexual behaviors, and diminished depressive-like behaviors, where transitions depend on dopamine (DA). Using DA sensor photometry and projection-targeted chemogenetics, we reveal that elevated DA release in specific brain regions mediates distinct behavioral changes in affective state transitions. Acute sleep loss induces DA-dependent enhancement in dendritic spine density and uncaging-evoked dendritic spinogenesis in the medial prefrontal cortex, whereas optically mediated disassembly of enhanced plasticity reverses the antidepressant effects of sleep deprivation on learned helplessness. These findings demonstrate that brain-wide dopaminergic pathways control sleep-loss-induced polymodal affective state transitions.
Topics: Humans; Mice; Animals; Dopamine; Sleep Deprivation; Brain; Sleep; Emotions
PubMed: 37922904
DOI: 10.1016/j.neuron.2023.10.002 -
Nature Reviews. Neuroscience Nov 2023Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial... (Review)
Review
Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E-TC begins with the activation of glutamate-gated N-methyl-D-aspartate-type receptors and voltage-gated L-type Ca channels at the membrane and culminates in the activation of transcription factors in the nucleus. These receptors and ion channels mediate E-TC through mechanisms that include long-range signalling from the synapse to the nucleus and local interactions within dendritic spines, among other possibilities. Growing experimental evidence links these E-TC mechanisms to late-phase long-term potentiation and learning and memory. These advances in our understanding of the molecular mechanisms of E-TC mean that future efforts can focus on understanding its mesoscale functions and how it regulates neuronal network activity and behaviour in physiological and pathological conditions.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Neuronal Plasticity; Long-Term Potentiation; Neurons; Synapses; Gene Expression; Hippocampus
PubMed: 37773070
DOI: 10.1038/s41583-023-00742-5 -
Brain : a Journal of Neurology Oct 2023Alzheimer's disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and...
Alzheimer's disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles and a significant decrease in the density of neuronal dendritic spines. Cdc42 is a member of the small G protein family that plays an important role in regulating synaptic plasticity and is regulated by Cdc42GAP, which switches Cdc42 from active GTP-bound to inactive GDP-bound states regulating downstream pathways via effector proteins. However, few studies have focused on Cdc42 in the progression of Alzheimer's disease. In a heterozygous Cdc42GAP mouse model that exhibited elevated Cdc42-GTPase activity accompanied by increased Cdc42-PAK1-cofilin signalling, we found impairments in cognitive behaviours, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer's disease, including phosphorylated tau (p-T231, AT8), along with increased soluble and insoluble Aβ1-42 and Aβ1-40, which are consistent with typical Alzheimer's disease mice. Interestingly, these impairments increased significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggested that Cdc42GAP deficiency induces and accelerates Alzheimer's disease-like phenotypes through activation of GSK-3β by dephosphorylation at Ser9, Ser389 and/or phosphorylation at Tyr216. In addition, overexpression of dominant-negative Cdc42 in the primary hippocampal and cortical neurons of heterozygous Cdc42GAP mice reversed synaptic loss and tau hyperphosphorylation. Importantly, the Cdc42 signalling pathway, Aβ1-42, Aβ1-40 and GSK-3β activity were increased in the cortical sections of Alzheimer's disease patients compared with those in healthy controls. Together, these data indicated that Cdc42GAP is involved in regulating Alzheimer's disease-like phenotypes such as cognitive deficits, dendritic spine loss, phosphorylated tau (p-T231, AT8) and increased soluble and insoluble Aβ1-42 and Aβ1-40, possibly through the activation of GSK-3β, and these impairments increased significantly with age. Thus, we provide the first evidence that Cdc42 is involved in the progression of Alzheimer's disease-like phenotypes, which may provide new targets for Alzheimer's disease treatment.
Topics: Animals; Humans; Mice; Actins; Alzheimer Disease; Glycogen Synthase Kinase 3 beta; Neurons; Phenotype; Phosphorylation; tau Proteins; GTPase-Activating Proteins
PubMed: 37254741
DOI: 10.1093/brain/awad184 -
Neuron Jul 2023Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the...
Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the initiation, transition, and maintenance of neuropathic pain. Furthermore, an antisense oligonucleotides (ASO) targeting spinal Tiam1 persistently alleviate neuropathic pain sensitivity. Our findings suggest that Tiam1-coordinated synaptic functional and structural plasticity underlies the pathophysiology of neuropathic pain and that intervention of Tiam1-mediated maladaptive synaptic plasticity has long-lasting consequences in neuropathic pain management.
Topics: Animals; Chronic Pain; Guanine Nucleotide Exchange Factors; Neuronal Plasticity; Actins; Neuralgia
PubMed: 37146610
DOI: 10.1016/j.neuron.2023.04.010 -
Nature Oct 2023The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse... (Comparative Study)
Comparative Study
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
Topics: Adolescent; Animals; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Mice; Young Adult; Cognition; Dendritic Spines; Gestational Age; Macaca; Neurons; Post-Synaptic Density; Proteomics; Rho Guanine Nucleotide Exchange Factors; Signal Transduction; Species Specificity; Synapses
PubMed: 37704727
DOI: 10.1038/s41586-023-06542-2 -
ELife Dec 2023General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their...
General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.
Topics: Humans; Mice; Animals; Microglia; Brain; Neurons; Consciousness; Anesthesia, General
PubMed: 38131301
DOI: 10.7554/eLife.92252 -
Synapse (New York, N.Y.) Sep 2023Schizophrenia is a chronic disease presented with psychotic symptoms, negative symptoms, impairment in the reward system, and widespread neurocognitive deterioration.... (Review)
Review
Schizophrenia is a chronic disease presented with psychotic symptoms, negative symptoms, impairment in the reward system, and widespread neurocognitive deterioration. Disruption of synaptic connections in neural circuits is responsible for the disease's development and progression. Because deterioration in synaptic connections results in the impaired effective processing of information. Although structural impairments of the synapse, such as a decrease in dendritic spine density, have been shown in previous studies, functional impairments have also been revealed with the development of genetic and molecular analysis methods. In addition to abnormalities in protein complexes regulating exocytosis in the presynaptic region and impaired vesicle release, especially, changes in proteins related to postsynaptic signaling have been reported. In particular, impairments in postsynaptic density elements, glutamate receptors, and ion channels have been shown. At the same time, effects on cellular adhesion molecular structures such as neurexin, neuroligin, and cadherin family proteins were detected. Of course, the confusing effect of antipsychotic use in schizophrenia research should also be considered. Although antipsychotics have positive and negative effects on synapses, studies indicate synaptic deterioration in schizophrenia independent of drug use. In this review, the deterioration in synapse structure and function and the effects of antipsychotics on the synapse in schizophrenia will be discussed.
Topics: Humans; Schizophrenia; Antipsychotic Agents; Synapses; Signal Transduction
PubMed: 37210696
DOI: 10.1002/syn.22276 -
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 -
The Neuroscientist : a Review Journal... Jul 2023The brain has the powerful ability to transform experiences into anatomic maps and continuously integrate massive amounts of information to form new memories. The manner... (Review)
Review
The brain has the powerful ability to transform experiences into anatomic maps and continuously integrate massive amounts of information to form new memories. The manner in which the brain performs these processes has been investigated extensively for decades. Emerging reports suggest that dendritic spines are the structural basis of information storage. The complex orchestration of functional and structural dynamics of dendritic spines is associated with learning and memory. Owing to advancements in techniques, more precise observations and manipulation enable the investigation of dendritic spines and provide clues to the challenging question of how memories reside in dendritic spines. In this review, we summarize the remarkable progress made in revealing the role of dendritic spines in fear memory and the techniques used in this field.
PubMed: 37480273
DOI: 10.1177/10738584231185530 -
Frontiers in Cellular Neuroscience 2023Epilepsy is a chronic central nervous system (CNS) disease associated with high morbidity. To date, there is no known disease-modifying therapy for epilepsy. A leading... (Review)
Review
Epilepsy is a chronic central nervous system (CNS) disease associated with high morbidity. To date, there is no known disease-modifying therapy for epilepsy. A leading hypothesis for a mechanism of epileptogenesis is the generation of aberrant neuronal networks. Although the underlying biological mechanism is not clear, scientific evidence indicates that it is associated with a hyperexcitable synchronous neuronal network and active dendritic spine plasticity. Changes in dendritic spine morphology are related to altered expression of synaptic cytoskeletal proteins, inflammatory molecules, neurotrophic factors, and extracellular matrix signaling. However, it remains to be determined if these aberrant dendritic spine formations lead to neuronal hyperexcitability and abnormal synaptic connections or whether they constitute an underlying mechanism of seizure susceptibility. Focusing on dendritic spine machinery as a potential target for medications could limit or reverse the development of epilepsy.
PubMed: 37601280
DOI: 10.3389/fncel.2023.1173694