Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation-TTLL glutamylases vs. CCP deglutamylases-accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.
- MeSH
- Hippocampus metabolism cytology MeSH
- Polyglutamic Acid * metabolism MeSH
- Microtubules * metabolism MeSH
- Motor Neurons * metabolism MeSH
- Mice MeSH
- Neuromuscular Junction metabolism MeSH
- Synaptic Transmission MeSH
- Neurons * metabolism MeSH
- Neuronal Plasticity * physiology MeSH
- Peptide Synthases metabolism genetics MeSH
- Protein Processing, Post-Translational MeSH
- Spastin metabolism MeSH
- Synapses metabolism MeSH
- Tubulin metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cannabinoid CB1 receptors have been shown to regulate wide array of functions ranging from homeostasis to the cognitive functioning but recent data support the hypothesis that astrocytes also operate as a mediator of synaptic plasticity and contribute to cognition and learning. The receptor heterogeneity plays a key role in understanding the molecular mechanisms underlying these processes. Despite the fact that the majority of CB1 receptors act on neurons, studies have revealed that cannabinoids have direct control over astrocytes, including energy generation and neuroprotection. The tripartite synapse connects astrocytes to neurons and allows them to interact with one another and the astrocytes are key players in synaptic plasticity, which is associated with cognitive functions. This review focuses on our growing understanding of the intricate functions of astroglial CB1 that underpin physiological brain function, and in Alzheimer's disease.
- MeSH
- Alzheimer Disease * MeSH
- Astrocytes MeSH
- Endocannabinoids MeSH
- Cognitive Dysfunction * MeSH
- Humans MeSH
- Neurons MeSH
- Neuronal Plasticity physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
All components of the CNS are surrounded by a diffuse extracellular matrix (ECM) containing chondroitin sulphate proteoglycans (CSPGs), heparan sulphate proteoglycans (HSPGs), hyaluronan, various glycoproteins including tenascins and thrombospondin, and many other molecules that are secreted into the ECM and bind to ECM components. In addition, some neurons, particularly inhibitory GABAergic parvalbumin-positive (PV) interneurons, are surrounded by a more condensed cartilage-like ECM called perineuronal nets (PNNs). PNNs surround the soma and proximal dendrites as net-like structures that surround the synapses. Attention has focused on the role of PNNs in the control of plasticity, but it is now clear that PNNs also play an important part in the modulation of memory. In this review we summarize the role of the ECM, particularly the PNNs, in the control of various types of memory and their participation in memory pathology. PNNs are now being considered as a target for the treatment of impaired memory. There are many potential treatment targets in PNNs, mainly through modulation of the sulphation, binding, and production of the various CSPGs that they contain or through digestion of their sulphated glycosaminoglycans.
- MeSH
- Chondroitin Sulfate Proteoglycans * metabolism MeSH
- Dendrites metabolism MeSH
- Extracellular Matrix * metabolism MeSH
- Neurons metabolism MeSH
- Neuronal Plasticity physiology MeSH
- Synapses metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- Keywords
- vzrušivost,
- MeSH
- Humans MeSH
- Brain anatomy & histology MeSH
- Synaptic Transmission physiology MeSH
- Nervous System Physiological Phenomena MeSH
- Neurobiology * MeSH
- Neurons cytology physiology MeSH
- Neuronal Plasticity MeSH
- Neurotransmitter Agents pharmacology physiology classification MeSH
- Synapses physiology MeSH
- Terminology as Topic * MeSH
- Check Tag
- Humans MeSH
Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.
- MeSH
- Dendritic Spines MeSH
- Membrane Proteins physiology MeSH
- Intercellular Signaling Peptides and Proteins genetics MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Neurons MeSH
- Neuronal Plasticity MeSH
- Autism Spectrum Disorder * MeSH
- Nerve Tissue Proteins genetics physiology MeSH
- Semaphorins * MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The perineuronal net (PNN) is a mesh-like proteoglycan structure on the neuronal surface which is involved in regulating plasticity. The PNN regulates plasticity via multiple pathways, one of which is direct regulation of synapses through the control of AMPA receptor mobility. Since neuronal pentraxin 2 (Nptx2) is a known regulator of AMPA receptor mobility and Nptx2 can be removed from the neuronal surface by PNN removal, we investigated whether Nptx2 has a function in the PNN. We found that Nptx2 binds to the glycosaminoglycans hyaluronan and chondroitin sulphate E in the PNN. Furthermore, in primary cortical neuron cultures, the addition of NPTX2 to the culture medium enhances PNN formation during PNN development. These findings suggest Nptx2 as a novel PNN binding protein with a role in the mechanism of PNN formation.
- MeSH
- C-Reactive Protein metabolism MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Nerve Net chemistry cytology metabolism MeSH
- Neurons chemistry metabolism MeSH
- Neuronal Plasticity physiology MeSH
- Satellite Cells, Perineuronal chemistry metabolism MeSH
- Rats, Sprague-Dawley MeSH
- Nerve Tissue Proteins metabolism MeSH
- Protein Binding physiology MeSH
- Visual Cortex chemistry cytology metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In neural computation, the essential information is generally encoded into the neurons via their spiking configurations, activation values or (attractor) dynamics. The synapses and their associated plasticity mechanisms are, by contrast, mainly used to process this information and implement the crucial learning features. Here, we propose a novel Turing complete paradigm of neural computation where the essential information is encoded into discrete synaptic states, and the updating of this information achieved via synaptic plasticity mechanisms. More specifically, we prove that any 2-counter machine-and hence any Turing machine-can be simulated by a rational-weighted recurrent neural network employing spike-timing-dependent plasticity (STDP) rules. The computational states and counter values of the machine are encoded into discrete synaptic strengths. The transitions between those synaptic weights are then achieved via STDP. These considerations show that a Turing complete synaptic-based paradigm of neural computation is theoretically possible and potentially exploitable. They support the idea that synapses are not only crucially involved in information processing and learning features, but also in the encoding of essential information. This approach represents a paradigm shift in the field of neural computation.
Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.
- MeSH
- Receptors, AMPA genetics metabolism MeSH
- Humans MeSH
- Intellectual Disability genetics metabolism MeSH
- Mutation physiology MeSH
- Neuronal Plasticity physiology MeSH
- Fragile X Syndrome genetics metabolism MeSH
- Protein Transport physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Hippocampal place cells represent different environments with distinct neural activity patterns. Following an abrupt switch between two familiar configurations of visual cues defining two environments, the hippocampal neural activity pattern switches almost immediately to the corresponding representation. Surprisingly, during a transient period following the switch to the new environment, occasional fast transitions between the two activity patterns (flickering) were observed (Jezek, Henriksen, Treves, Moser, & Moser, ). Here we show that an attractor neural network model of place cells with connections endowed with short-term synaptic plasticity can account for this phenomenon. A memory trace of the recent history of network activity is maintained in the state of the synapses, allowing the network to temporarily reactivate the representation of the previous environment in the absence of the corresponding sensory cues. The model predicts that the number of flickering events depends on the amplitude of the ongoing theta rhythm and the distance between the current position of the animal and its position at the time of cue switching. We test these predictions with new analysis of experimental data. These results suggest a potential role of short-term synaptic plasticity in recruiting the activity of different cell assemblies and in shaping hippocampal activity of behaving animals.
- MeSH
- Action Potentials physiology MeSH
- Time Factors MeSH
- Electroencephalography MeSH
- Hippocampus cytology MeSH
- Rats MeSH
- Brain Mapping MeSH
- Models, Neurological * MeSH
- Nerve Net physiology MeSH
- Neurons physiology MeSH
- Neuronal Plasticity physiology MeSH
- Cues MeSH
- Spatial Memory physiology MeSH
- Photic Stimulation MeSH
- Theta Rhythm physiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Keywords
- synaptogeneze,
- MeSH
- Anesthetics, Dissociative pharmacology adverse effects therapeutic use MeSH
- Excitatory Amino Acid Antagonists pharmacology adverse effects therapeutic use MeSH
- Antidepressive Agents pharmacology adverse effects therapeutic use MeSH
- Bipolar Disorder drug therapy MeSH
- Anesthesia, General MeSH
- Depressive Disorder, Treatment-Resistant drug therapy MeSH
- Depressive Disorder, Major drug therapy MeSH
- Depressive Disorder * drug therapy MeSH
- Ketamine * pharmacology adverse effects therapeutic use MeSH
- Humans MeSH
- Brain-Derived Neurotrophic Factor drug effects MeSH
- Neuronal Plasticity * drug effects MeSH
- Receptors, N-Methyl-D-Aspartate drug effects MeSH
- Suicidal Ideation MeSH
- Synapses drug effects MeSH
- TOR Serine-Threonine Kinases MeSH
- Drug Administration Routes MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
