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Neuropharmacology Jan 2016IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular... (Review)
Review
IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
Topics: Actin Cytoskeleton; Animals; Brain; Cell Membrane; Dendritic Spines; Humans; Mental Disorders; Mice; Nerve Tissue Proteins; Phenotype; Post-Synaptic Density; Protein Interaction Domains and Motifs; RNA, Messenger; Receptors, N-Methyl-D-Aspartate
PubMed: 26275848
DOI: 10.1016/j.neuropharm.2015.06.019 -
The Journal of Comparative Neurology Apr 2021Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by...
Lafora disease (LD) is a genetic and fatal form of neurodegenerative disorder characterized by myoclonic epilepsy and cognitive deficits. LD is caused by loss-of-function mutations in the EPM2A or the NHLRC1 gene. A major hallmark of LD is the presence of abnormal glycogen aggregates in neurons and other tissues. Functional studies on the genes have, therefore, mostly focused on glycogen metabolism. The physiological basis of cognitive deficits in LD is thus largely unexplored. Alterations in dendritic spine morphology are known in neurodevelopmental and neuropsychiatric disorders. We, therefore, analyzed the dendritic spine morphologies in pyramidal neurons of the hippocampal and Cortical layer V of the Epm2a or Nhlrc1 knockout mice brain. We found a significant increase in the density, length, and reduction in the width of the dendritic spines in Postnatal day 21 to 12-month-old LD animals. Similar observations were made in the primary cultures of neurons derived from the hippocampi of the embryonic brain, suggesting that the aberrant spine phenotype could be a developmental defect in LD. We also looked at the cognitive and behavioral deficits as a possible readout of the spine abnormalities. The LD animals exhibited hyperactivity, reduced anxiety-like behavior, and deficits in the spatial and nonspatial memory. Such abnormalities were seen in the younger (1-2 months) as well as the older (7-8 months) age groups. Taken together, our results suggest that the dendritic spine abnormalities are primary developmental defects in the LD model and these defects might underlie some of the symptoms, including cognitive deficits, in LD.
Topics: Animals; Cells, Cultured; Cerebral Cortex; Cognitive Dysfunction; Dendritic Spines; Female; Hippocampus; Lafora Disease; Male; Memory; Mice; Mice, Knockout; Pregnancy; Protein Tyrosine Phosphatases, Non-Receptor; Ubiquitin-Protein Ligases
PubMed: 32785985
DOI: 10.1002/cne.25006 -
Progress in Neurobiology Jan 2014Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala... (Review)
Review
Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.
Topics: Animals; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Dendritic Spines; Humans; Stress, Psychological
PubMed: 24211850
DOI: 10.1016/j.pneurobio.2013.10.005 -
Neurochemistry International 2007Dendritic spines are the postsynaptic receptive regions of most excitatory synapses, and their morphological plasticity play a pivotal role in higher brain functions,... (Review)
Review
Dendritic spines are the postsynaptic receptive regions of most excitatory synapses, and their morphological plasticity play a pivotal role in higher brain functions, such as learning and memory. The dynamics of spine morphology is due to the actin cytoskeleton concentrated highly in spines. Filopodia, which are thin and headless protrusions, are thought to be precursors of dendritic spines. Drebrin, a spine-resident side-binding protein of filamentous actin (F-actin), is responsible for recruiting F-actin and PSD-95 into filopodia, and is suggested to govern spine morphogenesis. Interestingly, some recent studies on neurological disorders accompanied by cognitive deficits suggested that the loss of drebrin from dendritic spines is a common pathognomonic feature of synaptic dysfunction. In this review, to understand the importance of actin-binding proteins in spine morphogenesis, we first outline the well-established knowledge pertaining to the actin cytoskeleton in non-neuronal cells, such as the mechanism of regulation by small GTPases, the equilibrium between globular actin (G-actin) and F-actin, and the distinct roles of various actin-binding proteins. Then, we review the dynamic changes in the localization of drebrin during synaptogenesis and in response to glutamate receptor activation. Because side-binding proteins are located upstream of the regulatory pathway for actin organization via other actin-binding proteins, we discuss the significance of drebrin in the regulatory mechanism of spine morphology through the reorganization of the actin cytoskeleton. In addition, we discuss the possible involvement of an actin-myosin interaction in the morphological plasticity of spines.
Topics: Actin Cytoskeleton; Actins; Animals; Dendritic Spines; Humans; Microfilament Proteins; Monomeric GTP-Binding Proteins; Neuronal Plasticity; Neuropeptides; Synapses
PubMed: 17590478
DOI: 10.1016/j.neuint.2007.04.029 -
Brain Research Dec 2007Most excitatory synapses in the CNS form on dendritic spines, tiny protrusions from the dendrites of excitatory neurons. As such, spines are likely loci of synaptic... (Review)
Review
Most excitatory synapses in the CNS form on dendritic spines, tiny protrusions from the dendrites of excitatory neurons. As such, spines are likely loci of synaptic plasticity. Spines are dynamic structures, but the functional consequences of dynamic changes in these structures in the mature brain are unclear. Changes in spine density, morphology, and motility have been shown to occur with paradigms that induce synaptic plasticity, as well as altered sensory experience and neuronal activity. These changes potentially lead to an alteration in synaptic connectivity and strength between neuronal partners, affecting the efficacy of synaptic communication. Here, we review the formation and modification of excitatory synapses on dendritic spines as it relates to plasticity in the central nervous system after the initial phase of synaptogenesis. We will also discuss some of the molecular links that have been implicated in both synaptic plasticity and the regulation of spine morphology.
Topics: Animals; Central Nervous System; Dendritic Spines; Neuronal Plasticity; Neurons; Synapses
PubMed: 16600191
DOI: 10.1016/j.brainres.2006.02.094 -
Neural Plasticity 2016
Topics: Animals; Dendritic Spines; Humans; Neuronal Plasticity
PubMed: 27127656
DOI: 10.1155/2016/2078121 -
Current Opinion in Neurobiology Feb 2011Dendritic spines are small actin-rich protrusions on the surface of dendrites whose morphological and molecular plasticity play key roles in learning and memory. Both... (Review)
Review
Dendritic spines are small actin-rich protrusions on the surface of dendrites whose morphological and molecular plasticity play key roles in learning and memory. Both the form and function of spines are critically dependent on the actin cytoskeleton. However, new research, using electron microscopy and live-cell super-resolution microscopy indicates that the actin cytoskeleton is more complex and dynamic than originally thought. Also, exciting recent studies from several labs indicate that microtubules, once thought to be restricted to the dendrite shaft, can make excursions into the most distal regions of dendritic spines. Moreover, microtubule invasions of spines appear to be associated with changes in synaptic activity. Thus, it is likely that dynamic interactions between microtubules and actin filaments within dendritic spines play important roles in dendritic spine plasticity.
Topics: Actins; Animals; Cytoskeleton; Dendritic Spines; Humans; Microtubules; Neuronal Plasticity
PubMed: 20832290
DOI: 10.1016/j.conb.2010.08.013 -
Synapse (New York, N.Y.) Sep 2022Parkinson's disease (PD) is a well-known neurodegenerative disorder associated with a high risk in middle-aged and elderly individuals, severely impacting the patient's...
Parkinson's disease (PD) is a well-known neurodegenerative disorder associated with a high risk in middle-aged and elderly individuals, severely impacting the patient's quality of life. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is frequently used to establish PD in animals. Dendritic spines are dendritic processes that form the foundation of learning and memory. Reportedly, dendritic spine density of striatal medium spiny neurons (MSNs) declines in PD, and this decline has been associated with PD progression; however, the underlying mechanism remains elusive. Herein, we used the MPTP animal model to examine whether serum-induced kinase (SNK) and spine-associated Rap guanosine triphosphatase (SPAR) contribute to decreased dendritic spine density in striatal MSNs. MPTP was used to establish the animal model, which exhibits motor function impairment and dopaminergic cell loss. To assess spine density, Golgi staining was performed to count striatal dendritic spines, which were reduced in the MPTP group when compared with those in the normal control group. Immunohistochemistry was performed to analyze changes in SNK and SPAR expression. MPTP treatment significantly increased the expression of SNK in striatal MSNs, whereas that of SPAR was significantly decreased when compared with the normal control group. These findings offer clues to further explore the mechanism of declining dendritic spine density in patients with PD and provide evidence for potential target identification in PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dendritic Spines; Disease Models, Animal; Dopaminergic Neurons; Guanosine; Mice; Mice, Inbred C57BL; Parkinson Disease; Quality of Life
PubMed: 36008099
DOI: 10.1002/syn.22249 -
The Neuroscientist : a Review Journal... Feb 2009Synaptic plasticity depends on the generation, modification and disconnection of synapses. An excitatory synapse is connected to a specialized dendritic compartment... (Review)
Review
Synaptic plasticity depends on the generation, modification and disconnection of synapses. An excitatory synapse is connected to a specialized dendritic compartment called a spine, which undergoes activity-induced remodeling. Here, we discuss a signaling pathway that transduces neuronal activity into the remodeling of spine through p38 mitogen-activated protein kinase (MAPK) and N-cadherin. Dendritic spines change their morphology and density in response to neuronal activity. In the early phase, posttranslational modifications of synaptic molecules regulate spine morphology, whereas activity-induced gene products reduce spine density in the late phase. One of the targets of these mechanisms is N-cadherin. An activity-induced protocadherin, arcadlin, stimulates thousand and one 2beta (TAO2beta) kinase, which in turn activates p38 MAPK through MAPK kinase 3 (MEK3), resulting in the endocytosis of N-cadherin and the decrease in spine number. This pathway also underlies the mechanism of the spine decrease in neuronal disorders, such as Alzheimer's disease and epilepsy. Development of new p38 MAPK inhibitors brings a ray of hope with respect to the development of more effective therapies for these patients.
Topics: Animals; Cadherins; Dendritic Spines; Models, Biological; Neuronal Plasticity; Neurons; Synapses; p38 Mitogen-Activated Protein Kinases
PubMed: 19218233
DOI: 10.1177/1073858408324024 -
Molecular and Cellular Neurosciences Jun 2021Cognitive comorbidities often follow early-life seizures (ELS), especially in the setting of autism and other neurodevelopmental syndromes. However, there is an...
Cognitive comorbidities often follow early-life seizures (ELS), especially in the setting of autism and other neurodevelopmental syndromes. However, there is an incomplete understanding of whether neuronal and synaptic development are concomitantly dysregulated. We have previously shown that hypoxia-induced seizures (HS) in postnatal day (P)10 rats increase acute and later-life hippocampal glutamatergic neurotransmission and spontaneous recurrent seizures, and impair cognition and behavior. As dendritic spines critically regulate synaptic function, we hypothesized that ELS can induce developmentally specific changes in dendritic spine maturation. At intervals during one month following HS in P10 rats, we assessed dendritic spine development on pyramidal neurons in the stratum radiatum of hippocampal area CA1. Compared to control rats in which spine density significantly decreased from P10 to early adulthood (P38), post-seizure rats failed to show a developmental decrease in spine density, and spines from P38 post-seizure rats appeared more immature-shaped (long, thin). In addition, compared to P38 control rats, post-seizure P38 rats expressed significantly more synaptic PSD-95, a marker of mature synapses. These changes were preceded by a transient increase in hippocampal expression of cofilin phosphorylated at Ser3, representing a decrease in cofilin activity. These results suggest that early-life seizures may impair normal dendritic spine maturation and pruning in CA1 during development, resulting in an excess of less efficient synapses, via activity-dependent modification of actin-regulating proteins such as cofilin. Given that multiple neurodevelopmental disorders show similar failures in developmental spine pruning, the current findings may represent a deficit in structural plasticity that could be a component of a mechanism leading to later-life cognitive consequences associated with early-life seizures.
Topics: Actin Depolymerizing Factors; Animals; CA1 Region, Hippocampal; Dendritic Spines; Hypoxia, Brain; Male; Rats; Rats, Long-Evans; Seizures
PubMed: 34015497
DOI: 10.1016/j.mcn.2021.103629