Abstract
Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs are critically involved in brain function and dysfunction. In this paper, we will review studies on the roles and underlying mechanisms of LIMKs in the regulation of long-term potentiation (LTP) and depression (LTD), the most extensively studied forms of long-lasting synaptic plasticity widely regarded as cellular mechanisms underlying learning and memory. We will also discuss the involvement of LIMKs in the regulation of the dendritic spine, the structural basis of synaptic plasticity, and memory formation. Finally, we will discuss recent progress on investigations of LIMKs in neurological and mental disorders, including Alzheimer’s, Parkinson’s, Williams–Beuren syndrome, schizophrenia, and autism spectrum disorders.
Highlights
Long-term modifications in the efficacy of signal transmission at excitatory synapses, such as long-term potentiation (LTP) and long-term depression (LTD), are considered to be the major cellular mechanisms that contribute to the plasticity of neuronal circuits underlying learning and memory [1,2,3,4,5,6]
In GluA2 KO mice, mGluR-LTD was impaired, but this impairment was rescued in LIMK1 KO mice or by manipulations to inhibit cofilin phosphorylation [93]. These results suggest that mGluR activation triggers GluA2-dependent inhibition of Rac1-LIMK1 and dephosphorylation of cofilin, which facilitates amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) internalization, spine shrinkage, and mGluR-LTD [93]
Changes in LIM-domain kinase proteins (LIMKs) signaling, including upstream regulators and downstream targets, are widely reported in brain disorders and in some cases, manipulations of LIMK1 improve synaptic and behavioural functions associated with these disorders
Summary
Long-term modifications in the efficacy of signal transmission at excitatory synapses, such as long-term potentiation (LTP) and long-term depression (LTD), are considered to be the major cellular mechanisms that contribute to the plasticity of neuronal circuits underlying learning and memory [1,2,3,4,5,6]. Since the actin cytoskeleton is the major structural component of dendritic spines, many studies have shown that actin reorganization plays a central role in spine formation, maintenance, and dynamic changes under both basal conditions and activity-dependent neural plasticity [31,32,34,35,36,37,38,39,40]. As key regulators of the actin cytoskeleton, LIM-domain kinase proteins (LIMKs) play a critical role in synaptic development and plasticity. Several studies have identified transcription factors as potential targets for LIMK1 in neurons These include cAMP response element-binding protein (CREB) [67] and Nurr1 [68].
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