ABSTRACT
Filamentous actin (F-actin) is highly enriched in the dendritic spine, a specialized postsynaptic structure on which the great majority of the excitatory synapses are formed in the mammalian central nervous system (CNS). The protein kinases of the Lim-kinase (LIMK) family are potent regulators of actin dynamics in many cell types and they are abundantly expressed in the CNS, including the hippocampus. Using a combination of genetic manipulations and electrophysiological recordings in mice, we have demonstrated that LIMK-1 signaling is important in vivo in the regulation of the actin cytoskeleton, spine morphology, and synaptic function, including hippocampal long-term potentiation (LTP), a prominent form of long lasting synaptic plasticity thought to be critical to memory formation. Our results provide strong genetic evidence that LIMK and its substrate ADF/cofilin are involved in spine morphology and synaptic properties and are consistent with the notion that the Rho family small GTPases and the actin cytoskeleton are critical to spine structure and synaptic regulation.
Subject(s)
Actins/physiology , Central Nervous System/physiology , Cytoskeleton/physiology , Protein Kinases/physiology , Synapses/physiology , Actin Depolymerizing Factors , Animals , Cognition , Dendrites/metabolism , Destrin , Lim Kinases , Long-Term Potentiation/physiology , Mice , Microfilament Proteins/metabolism , Receptors, Glutamate/physiology , rhoB GTP-Binding Protein/metabolismABSTRACT
In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.
