Trends in Neurosciences
Volume 31, Issue 8, August 2008, Pages 419-427
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Review
Dendritic spine dynamics – a key role for kalirin-7

https://doi.org/10.1016/j.tins.2008.06.001Get rights and content

Changes in the structure and function of dendritic spines contribute to numerous physiological processes such as synaptic transmission and plasticity, as well as behavior, including learning and memory. Moreover, altered dendritic spine morphogenesis and plasticity is an endophenotype of many neurodevelopmental and neuropsychiatric disorders. Hence, the molecular mechanisms that control spine plasticity and pathology have been under intense investigation over the past few years. A series of recent studies has improved our understanding of spine dynamics by establishing kalirin-7 as an important regulator of dendritic spine development as well as structural and functional plasticity, providing a model for the molecular control of structural plasticity and implicating kalirin-7 in synaptic pathology in several disorders including schizophrenia and Alzheimer's disease.

Section snippets

Dendritic spine plasticity mechanisms

In the mammalian forebrain, most excitatory synapses are located on dendritic spines, mushroom-shaped protrusions of dendrites [1]. Spine morphology modulates synaptic properties, including strength, stability, calcium dynamics, receptor content and the ability to undergo plasticity 2, 3. In the young brain, dendritic filopodia and spines are very dynamic, actively participating in synapse formation and elimination [4]. Spine plasticity driven by changes in synaptic activity contributes to the

Spine maturation: a role for EphB/kalirin-7/PAK signaling

Dendritic spine morphogenesis is a vital part of the process of synapse formation and maturation during CNS development, and it is highly regulated by several important signaling pathways. B-type ephrins and their EphB receptors are a family of intercellular adhesion-like molecules that control multiple aspects of neuronal development, including synapse formation and maturation, as well as synaptic structural and functional plasticity [32]. Activation of EphB receptors in neurons induces the

Activity-dependent spine structural and functional plasticity: a role for kalirin-7

Structural modification of the excitatory synapse in response to neuronal activity is a key component of experience-dependent development and plasticity in the developing and adult mammalian brain. Dendritic spine morphogenesis and synaptic function are strongly correlated in plasticity models such as sensory deprivation and environmental enrichment [3], and synaptic AMPA receptor (AMPAR) content is also influenced by spine size [2]. In pyramidal neurons, various forms of activity-dependent

Adhesion signaling and spine stability: a role for kalirin-7

In addition to its roles in ephrin- and activity-dependent dendritic spine remodeling, kalirin-7 is also crucial for the modulation of spine morphology by another class of trans-synaptic adhesion molecules, N-cadherins. Signaling by N-cadherins modulates synaptic plasticity, as well as spine morphology and stability 32, 36, 41. Xie and colleagues found that upon engagement of N-cadherin in cortical pyramidal neurons, kalirin-7 is recruited into complexes with N-cadherin-associated proteins

Protein signaling networks regulating spine dynamics

Numerous multidomain proteins with enzymatic activity have been found to participate in an ever-growing signaling pathway network in dendritic spines that regulates synaptic structure and function 44, 45. As the complexity of the signaling network governing dendritic spine dynamics increases, it is becoming clear that crosstalk between pathways is crucial for the convergence of signaling and appropriate structural or functional modification of the synapse. We discuss kalirin-7 as a model of a

Regulation of synapse structure in interneurons

Recent studies reveal that regulators of dendritic spine dynamics in pyramidal neurons can also play a role in aspiny synapse formation and maintenance in interneurons. The AMPAR subunit GluR2 [51] and the scaffolding protein Shank3 [52] have both been shown to induce spine formation in aspiny interneurons or cerebellar granule cells, but much less is known about the structural regulation of these aspiny synapses. An interesting recent finding is that kalirin-7 is also important for the

Synaptic pathology: a role for kalirin-7

Aberrant spine morphology is a hallmark of many neurodevelopmental, neuropsychiatric and neurodegenerative disorders, including autism spectrum disorders [9], Rett syndrome [10], fragile X syndrome [12], schizophrenia [13], mood disorders [56], stress [56], drug addiction [14], Alzheimer's disease [15], Parkinson's disease [17] and Huntington's disease [16]. The close relationship of synapse structure and function implicates spine dysgenesis in many of these diseases and, indeed, many of the

Conclusions and future directions

Answering several important remaining questions regarding the functions of kalirin-7 would significantly advance our understanding of the neurobiological implications of synaptic signaling and structural plasticity. It is hence of immediate interest to determine the role of kalirin-7 signaling in LTP or LTD in specific brain regions, such as the hippocampus, cortex, striatum or amygdala. Although genetic studies demonstrate a crucial role for regulators of Rho GTPase signaling in human

Acknowledgements

We thank Robert Sweet (University of Pittsburgh) and Jaime Grutzendler (Northwestern University) for useful comments, Zhong Xie for images and Michael Cahill and Kathryn Schoedel for proofreading the manuscript. Research described in the text has been funded by grants from NIH-NIMH (MH071316–01A1), NARSAD and NAAR (to P.P.).

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