Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders?

Fiala, John C.; Spaček, J; Harris, Kristen M.

doi:10.1016/s0165-0173(02)00158-3

Cited by 745 publications

(569 citation statements)

References 264 publications

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“…As synapses form, the number of filopodia declines and the number of spines increases, suggesting the involvement of dendritic filopodia in spine emergence (Zuo et al, 2005a,b). Decreased spine density and increased density of filopodia-like protrusions associated with several brain diseases lends further support to the notion that filopodia serve as precursors to spines (Fiala et al, 2002;Calabrese et al, 2006). However, no direct evidence illustrating the emergence of spines from filopodia has been found.…”

Section: Introductionmentioning

confidence: 80%

Paralemmin-1, a Modulator of Filopodia Induction Is Required for Spine Maturation

Arstikaitis

Gauthier-Campbell

Herrera

et al. 2008

MBoC

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Dendritic filopodia are thought to participate in neuronal contact formation and development of dendritic spines; however, molecules that regulate filopodia extension and their maturation to spines remain largely unknown. Here we identify paralemmin-1 as a regulator of filopodia induction and spine maturation. Paralemmin-1 localizes to dendritic membranes, and its ability to induce filopodia and recruit synaptic elements to contact sites requires protein acylation. Effects of paralemmin-1 on synapse maturation are modulated by alternative splicing that regulates spine formation and recruitment of AMPA-type glutamate receptors. Paralemmin-1 enrichment at the plasma membrane is subject to rapid changes in neuronal excitability, and this process controls neuronal activity-driven effects on protrusion expansion. Knockdown of paralemmin-1 in developing neurons reduces the number of filopodia and spines formed and diminishes the effects of Shank1b on the transformation of existing filopodia into spines. Our study identifies a key role for paralemmin-1 in spine maturation through modulation of filopodia induction. INTRODUCTIONDuring CNS excitatory synapse development, the formation of spines, bulbous protrusions enriched with F-actin, is essential for proper synaptic transmission and neuronal function (Hall and Nobes, 2000;Yuste and Bonhoeffer, 2004;Halpain et al., 2005;Matus, 2005;. Spines contain a plethora of proteins including neurotransmitter receptors, cytoskeleton-associated proteins, and cell adhesion molecules. Spines are pleomorphic protrusions that can be modified by changes in neuronal activity, which regulate actin-based motility (Fischer et al., 1998;Portera-Cailliau et al., 2003;Matus, 2005). Defects in spine maturation and function have been associated with several forms of mental retardation including Down, Rett, Fragile X, and fetal alcohol syndromes. Some of these disorders exhibit a reduction in spine size and density and the formation of long, thin filopodia-like structures (Hering and Sheng, 2001;Zoghbi, 2003).Although our knowledge of molecules that control the morphology and functional properties of dendritic spines has expanded, information about the structures from which spines emerge is lacking. Dendritic filopodia, thin protrusions ranging in length from 2 to 35 m, are thought to participate in synaptogenesis, dendritic branching and the development of spines. During synaptogenesis, filopodia decorate the dendrites of neurons. Studies show that dendritic filopodia exhibit highly dynamic protrusive motility during periods of active synaptogenesis (Dailey and Smith, 1996;Ziv and Smith, 1996;Marrs et al., 2001). Thus, filopodia are thought to function by extending and probing the environment for appropriate presynaptic partners, thereby aiding in synapse formation. These results are further supported by electron microscopy studies which show that synapses can be formed at the tip and base of dendritic filopodia (Fiala et al., 1998;Kirov et al., 2004). As synapses form, the number of filopodia d...

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Section: Introductionmentioning

confidence: 80%

Paralemmin-1, a Modulator of Filopodia Induction Is Required for Spine Maturation

Arstikaitis

Gauthier-Campbell

Herrera

et al. 2008

MBoC

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“…Similarly, Callahan et al [9] documented a progressive reduction of synaptophysin mRNA in single NFT-bearing neurons. In the context of the possible disconnection of corticocortical pathways in AD [30,32,48], dendritic spine pathology is thought to be secondary to abnormal afferent innervation [20,63,65,81]. In line with this hypothesis, Scheff et al reported in the only stereologic study available in this field a weak positive relationship between NFT densities in layer II of the entorhinal cortex and loss of synaptic contacts in the outer molecular layer of dentate gyrus (i.e.…”

Section: Discussionmentioning

confidence: 97%

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

Akram

Christoffel

Rocher

et al. 2008

Neurobiology of Aging

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The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer's disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.

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“…Dendritic spine abnormalities accompany neurological disorders such as mental retardation, autism and schizophrenia (27). Increased glial glutamate transporter levels and function are also associated with schizophrenia (4,28).…”

Section: Discussionmentioning

confidence: 99%

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

Carmona

Murai

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

182

173

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Increasing evidence indicates the importance of neuron-glia communication for synaptic function, but the mechanisms involved are not fully understood. We reported that the EphA4 receptor tyrosine kinase is in dendritic spines of pyramidal neurons of the adult hippocampus and regulates spine morphology. We now show that the ephrin-A3 ligand, which is located in the perisynaptic processes of astrocytes, is essential for maintaining EphA4 activation and normal spine morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.glial glutamate transporters ͉ hippocampus-dependent learning ͉ neuron-glia communication ͉ perisynaptic glial processes C ommunication between neurons and astrocytes plays an important role in synapse development and physiology. During development, astrocytes promote synapse formation and maturation (1, 2). Later on, astrocytes are actively involved in synaptic transmission by responding to synaptic activation and releasing gliotransmitters, which in turn modulate neuronal excitability and neurotransmission (1, 3). At excitatory synapses, astrocytes clear the majority of glutamate released into the synaptic cleft through their high-affinity transporters, GLAST and GLT-1 (4). This function is crucial for fine-tuning glutamatergic transmission and prevents accumulation of toxic levels of extracellular glutamate (5-7). Despite their importance in glutamate homeostasis, very little is known about the molecular mechanisms that regulate the expression and cell surface localization of glial glutamate transporters.Several members of the Eph family of receptor tyrosine kinases (comprising EphA and EphB receptors) and their cell surface-associated ephrin ligands are expressed in neurons of the hippocampus and cerebral cortex, where they have been implicated in synapse formation and the regulation of synaptic function and plasticity (8, 9). Signaling by Eph receptors is also involved in the development of dendritic spines, the specialized protrusions on dendrites that receive excitatory innervation. Typical spines have an enlarged head connected to the dendritic shaft by a constricted neck. Activation of dendritic EphB receptors by ephrin-B ligands has been shown to induce spine morphogenesis and maturation (8, 9). EphA receptors are important regulators of spine morphology in the adult. We have reported that EphA4 is localized on dendritic spines of pyramidal neurons in the m...

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Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders?

Cited by 745 publications

References 264 publications

Paralemmin-1, a Modulator of Filopodia Induction Is Required for Spine Maturation

Paralemmin-1, a Modulator of Filopodia Induction Is Required for Spine Maturation

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport

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