A role for synaptopodin and the spine apparatus in hippocampal synaptic plasticity

doi:10.1016/j.aanat.2006.06.013

Annals of Anatomy - Anatomischer Anzeiger

Volume 189, Issue 1, 1 February 2007, Pages 5-16

https://doi.org/10.1016/j.aanat.2006.06.013 Get rights and content

Summary

Spines are considered sites of synaptic plasticity in the brain and are capable of remodeling their shape and size. A molecule that has been implicated in spine plasticity is the actin-associated protein synaptopodin. This article will review a series of studies aimed at elucidating the role of synaptopodin in the rodent brain. First, the developmental expression of synaptopodin mRNA and protein were studied; secondly, the subcellular localization of synaptopodin in hippocampal principal neurons was analyzed using confocal microscopy as well as electron microscopy and immunogold labelling; and, finally, the functional role of synaptopodin was investigated using a synaptopodin-deficient mouse. The results of these studies are: (1) synaptopodin expression by hippocampal principal neurons develops during the first postnatal weeks and increases in parallel with the maturation of spines in the hippocampus. (2) Synaptopodin is sorted to the spine compartment, where it is tightly associated with the spine apparatus, an enigmatic organelle believed to be involved in calcium storage or local protein synthesis. (3) Synaptopodin-deficient mice generated by gene targeting are viable but lack the spine apparatus organelle. These mice show deficits in synaptic plasticity as well as impaired learning and memory. Taken together, these data implicate synaptopodin and the spine apparatus in the regulation of synaptic plasticity in the hippocampus. Future studies will be aimed at finding the molecular link between synaptopodin, the spine apparatus organelle, and synaptic plasticity.

Section snippets

Spines are sites of neuronal plasticity in brain

Spines are small appendages of dendrites that contain the postsynaptic elements of asymmetric synapses (Gray, 1959). In recent years, it has been well documented that spines are structurally highly dynamic and that their morphological parameters, i.e. their length and head size, influence the propagation of neuronal activity from the pre- to the postsynaptic neuron (Svoboda et al., 1996; Matsuzaki et al., 2001, Matsuzaki et al., 2004; Korkotian et al., 2004; Hayashi and Majewska, 2005; Segal,

Conclusions and outlook

The findings of the studies that were reviewed in this paper can be summarized as follows: (1) Synaptopodin is an actin-associated molecule that is expressed by neurons and kidney podocytes. During development, it is expressed fairly late in the hippocampus, in a sequence that correlates with the regional differentiation of the hippocampal formation and the appearance of mature spines. (2) In the adult brain, synaptopodin is preferentially sorted to spines. In spines, synaptopodin is tightly

Acknowledgments

The studies reviewed here were done in collaboration with Drs. Peter Mundel, Tobias Bonnhoeffer, Rolf Zeller, Aimee Zuniga, Guilia Good Stefani, Karin Schwarz, Kathrin Czarnecki, Tobias Merten, Stephanie Roth, and Guoping Feng, and were supported by the Deutsche Forschungsgemeinschaft (SFB 505; DE 551/8-1) and the German Israeli Foundation (GIF to T.D. and M.F.).

Supporting grant: This study was supported by the Deutsche Forschungsgemeinschaft (SFB 505; DE 551/8-1) and the German Israeli

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Modifications to cytoskeleton-associated proteins in dendritic spines underlie the adaptive plasticity involved in long term reference memory
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Spatial learning and memory enables individuals to orientate themselves in an external environment. Synaptic stimulation of dendritic spines on hippocampal place cells underlies adaptive cognitive performance, inducing plastic changes such as spinogenesis, pruning and structural interconversion. Such plastic changes are driven by complex molecular machinery that relies on several actin cytoskeleton-associated proteins (ACAP’s), these interacting with actin filaments in the postsynaptic density to guide the conformational changes to spines in accordance with the synaptic information they receive. However, the specific dynamics of the plastic changes in spines driven by ACAP’s are poorly understood. Adult rats exhibit efficient allocentric reference memory 30 days after training in a spatial learning paradigm in the Morris water maze. A Golgi study revealed this behavior to be associated with a reduction in both spine density and in mushroom spines, as well as a concomitant increase in thin spines. These changes were accompanied by the overexpression of mRNA encoding β-actin, Spinophilin and Cortactin, whilst the expression of Profilin, α-actinin, Drebrin, Synaptopodin and Myosin decreased. By contrast, no changes were evident in Cofilin, Gelsolin and Arp2/3 mRNA. From this analysis, it appears that neither spinogenesis nor new mushroom spines are necessary for long-term spatial information retrieval, while thin spines could be potentiated to retrieve pre-learned spatial information. Further studies that focus on the signaling pathways and their related molecules may shed further light on the molecular dynamics of the plastic changes to dendritic spines that underlie cognitive performance, both under normal and pathological conditions.
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Moreover, we were recently able to demonstrate that (3) SP/SA is also involved in the regulation of homeostatic synaptic plasticity (Vlachos et al., 2013a), which indicates that SP/SA could play an important role in adjusting the ability of neurons to express different forms of synaptic plasticity (Vlachos, 2012). Consistent with work on ER Ca2+ stores in synaptic plasticity, these studies further established SP/SA as a key regulator of synaptic plasticity (for reviews see Deller et al., 2007; Jedlicka et al., 2008; Segal et al., 2010; Vlachos, 2012). While the precise cellular and molecular mechanisms through which SP/SA affect different forms of synaptic plasticity warrant additional investigation, experimental evidence has been provided for changes in SP-expression, SP-cluster sizes and stacking of SAs to accompany the induction of synaptic plasticity (Vlachos et al., 2009, 2013a; see also Yamazaki et al., 2001; Fukazawa et al., 2003).
Work from the past 40 years has unraveled a wealth of information on the cellular and molecular mechanisms underlying synaptic plasticity and their relevance in physiological brain function. At the same time, it has been recognized that a broad range of neurological diseases may be accompanied by severe alterations in synaptic plasticity, i.e., ‘maladaptive synaptic plasticity’, which could initiate and sustain the remodeling of neuronal networks under pathological conditions. Nonetheless, our current knowledge on the specific contribution and interaction of distinct forms of synaptic plasticity (including metaplasticity and homeostatic plasticity) in the context of pathological brain states remains limited. This review focuses on recent experimental evidence, which highlights the fundamental role of endoplasmic reticulum-mediated Ca²⁺ signals in modulating the duration, direction, extent and type of synaptic plasticity. We discuss the possibility that intracellular Ca²⁺ stores may regulate synaptic plasticity and hence behavioral and cognitive functions at the interface between physiology and pathology.
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SP is found in a subset of dendritic spines (Bas Orth et al., 2005; Deller et al., 2003; Holbro et al., 2009; Vlachos et al., 2009), where it associates with the spine apparatus organelle (Gray, 1959; Spacek, 1985), while in the axon initial segment SP is enriched at cisternal organelles (e.g., Bas Orth et al., 2007; Sanchez-Ponce et al., 2012). SP has been linked to neuronal plasticity (for reviews see Deller et al., 2007; Segal et al., 2010; Vlachos, 2012) through the regulation of intracellular Ca2 + stores (Holbro et al., 2009; Korkotian and Segal, 2011; Vlachos et al., 2009) and/or the actin-cytoskeleton (Okubo-Suzuki et al., 2008). Interestingly, it has been suggested that SP regulates both Hebbian plasticity, i.e., long-term potentiation (LTP; Deller et al., 2003; Jedlicka et al., 2009; Vlachos et al., 2009; Yamazaki et al., 2001; Zhang et al., 2013), long-term depression (LTD; Holbro et al., 2009), and homeostatic synaptic plasticity (Vlachos et al., 2013).
Systemic inflammation is known to affect memory function through the activation of immune cells and the release of inflammatory cytokines. However, the neuronal targets by which inflammatory signaling pathways affect synaptic plasticity remain not well understood. Here, we addressed the question of whether systemic lipopolysaccharide (LPS)-induced inflammation influences the expression of Synaptopodin (SP). SP is an actin-binding protein, which is considered to control the ability of neurons to express synaptic plasticity by regulating the actin-cytoskeleton and/or intracellular Ca^2 + stores. This makes SP an interesting target molecule in the context of inflammation-induced alterations in synaptic plasticity. Using quantitative PCR (qPCR)-analysis and immunohistochemistry we here demonstrate that intraperitoneal LPS-injection in two-month old male Balb/c mice leads to a reduction in hippocampal SP-levels (area CA1; 24 h after injection). These changes are accompanied by a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses, similar to what is observed in SP-deficient mice. We therefore propose that systemic inflammation could exert its effects on neural plasticity, at least in part, through the down-regulation of SP in vivo.
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^☆: Lecture at the 101st meeting of the Anatomische Gesellschaft in Freiburg, April 7–10, 2006.

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A role for synaptopodin and the spine apparatus in hippocampal synaptic plasticity☆

Summary

Section snippets

Spines are sites of neuronal plasticity in brain

Conclusions and outlook

Acknowledgments

Brain Res. Mol. Brain Res.

Neuropharmacology

Trends Neurosci.

Curr. Opin. Neurobiol.

Neuron

Brain Res.

Neuron

Neuron

Curr. Opin. Neurobiol.

Neuron

Cell Calc.

Neuron

Cell Calc.

Curr. Biol.

Trends Neurosci.

Neuron

Neuron

Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner

J. Clin. Invest.

Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling

Nat. Cell Biol.

Lamina-specific distribution of synaptopodin, an actin-associated molecule essential for the spine apparatus, in identified principal cell dendrites of the mouse hippocampus

J. Comp. Neurol.

Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography

J. Comp. Neurol.

Development of the hippocampal region in the rat. II. Morphogenesis during embryonic and early postnatal life

J. Comp. Neurol.

LTP induction is associated with major ultrastructural changes of activated synapses

Proc. Natl. Acad. Sci. USA

Cytochemical localisation of calcium binding sites in adrenal chromaffin cells and their relation to secretion

Cell Tissue Res.

Identification of fodrin as a major calmodulin-binding protein in postsynaptic density preparations

J. Cell Biol.

Immunocytochemical localization of actin in dendritic spines of the cerebral cortex using colloidal gold as a probe

Cell. Mol. Neurobiol.

Postnatal development of synaptopodin expression in the rodent hippocampus

J. Comp. Neurol.

The dynamics of dendritic structures in developing hippocampal slices

J. Neurosci.

Actin-associated protein synaptopodin in the rat hippocampal formation: localization in the spine neck and close association with the spine apparatus of principal neurons

J. Comp. Neurol.

Laminar distribution of synaptopodin in normal and reeler mouse brain depends on the position of spine-bearing neurons

J. Comp. Neurol.

Synaptopodin-deficient mice lack a spine apparatus and show deficits in synaptic plasticity

Proc. Natl. Acad. Sci. USA

The actin cytoskeleton: integrating form and function at the synapse

Annu. Rev. Neurosci.

Evidence for the concentration of F-actin and myosin in synapses and in the plasmalemmal zone of axons

Eur. J. Cell Biol.

Developmental regulation of spine motility in the mammalian central nervous system

Proc. Natl. Acad. Sci. USA

A possible mechanism of morphometric changes in dendritic spines induced by stimulation

Cell. Mol. Neurobiol.

Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity

J. Cell Biol.

Long-lasting morphological changes in dendritic spines of dentate granular cells following stimulation of the entorhinal area

J. Neurocytol.

Glutamate receptors regulate actin-based plasticity in dendritic spines

Nat. Neurosci.