Kalirin-7 Is Required for Synaptic Structure and Function

Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2008; 28(47):12368-82. DOI: 10.1523/JNEUROSCI.4269-08.2008
Source: PubMed


Rho GTPases activated by GDP/GTP exchange factors (GEFs) play key roles in the developing and adult nervous system. Kalirin-7 (Kal7), the predominant adult splice form of the multifunctional Kalirin RhoGEF, includes a PDZ [postsynaptic density-95 (PSD-95)/Discs large (Dlg)/zona occludens-1 (ZO-1)] binding domain and localizes to the postsynaptic side of excitatory synapses. In vitro studies demonstrated that overexpression of Kal7 increased dendritic spine density, whereas reduced expression of endogenous Kal7 decreased spine density. To evaluate the role of Kal7 in vivo, mice lacking the terminal exon unique to Kal7 were created. Mice lacking both copies of the Kal7 exon (Kal7(KO)) grew and reproduced normally. Golgi impregnation and electron microscopy revealed decreased hippocampal spine density in Kal7(KO) mice. Behaviorally, Kal7(KO) mice showed decreased anxiety-like behavior in the elevated zero maze and impaired acquisition of a passive avoidance task, but normal behavior in open field, object recognition, and radial arm maze tasks. Kal7(KO) mice were deficient in hippocampal long-term potentiation. Western blot analysis confirmed the absence of Kal7 and revealed compensatory increases in larger Kalirin isoforms. PSDs purified from the cortices of Kal7(KO) mice showed a deficit in Cdk5, a kinase known to phosphorylate Kal7 and play an essential role in synaptic function. The early stages of excitatory synaptic development proceeded normally in cortical neurons prepared from Kal7(KO) mice, with decreased excitatory synapses apparent only after 21 d in vitro. Expression of exogenous Kal7 in Kal7(KO) neurons rescued this deficit. Kal7 plays an essential role in synaptic structure and function, affecting a subset of cognitive processes.

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Article: Kalirin-7 Is Required for Synaptic Structure and Function

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    • "However, because most of the previous studies rely on phenotypes of global KO mice (Carlson et al., 2011; Ma et al., 2008; Oh et al., 2010), the significance of developmental Rho GTPase signaling for adult cognition is not well understood. For example, global disruption of RacGEF kalirin-7 results in impaired acquisition of a passive avoidance task (Ma et al., 2008). However, because kalirin-7 functions in both synapse formation during development and spine plasticity in adulthood (Penzes and Jones, 2008), it is unclear if ka- lirin-7 during development or in adulthood is important for adult "
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    • "Kalirin plays an integral role in dendritic spine growth, morphogenesis, and activity-dependent plasticity (Xie et al. 2007; Cahill et al. 2009). Importantly , kalirin reduction is known to deplete PSD GluR1, NMDAR2B, and cause spine loss (Xie et al. 2007; Ma et al. 2008), and conversely, increased expression of kalirin-7 and -9 increases spine density (Ma et al. 2008; Deo et al. 2011). An important downstream target of kalirin signaling, p21- activated kinase, shows reduced activation in response to Ab in vitro and in vivo, and contributes to dendritic spine loss (Zhao et al. 2006). "
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    Journal of Neurochemistry 04/2013; 126(2). DOI:10.1111/jnc.12261 · 4.28 Impact Factor
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    • "A knockout mouse for the most prevalent form of Kalirin in the adult brain, Kalirin7, was generated by eliminating its unique 3′-exon (Kal7KO/KO) [13]. Kal7KO/KO mice have fewer dendritic spines in selected brain regions and exhibit impaired passive avoidance behavior, decreased anxiety-like behavior and accentuated locomotor sensitization to repeated cocaine treatment [13,24]. Cahill et al. [25] replaced Kalrn exons 27 and 28, which encode part of the first GEF domain, with the neomycin resistance gene, generating the KalGEF1KO/KO mouse [25]. "
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    ABSTRACT: Background The human KALRN gene, which encodes a complex, multifunctional Rho GDP/GTP exchange factor, has been linked to cardiovascular disease, psychiatric disorders and neurodegeneration. Examination of existing Kalrn knockout mouse models has focused only on neuronal phenotypes. However, Kalirin was first identified through its interaction with an enzyme involved in the synthesis and secretion of multiple bioactive peptides, and studies in C.elegans revealed roles for its orthologue in neurosecretion. Results We used a broad array of tests to evaluate the effects of ablating a single exon in the spectrin repeat region of Kalrn (KalSRKO/KO); transcripts encoding Kalrn isoforms containing only the second GEF domain can still be produced from the single remaining functional Kalrn promoter. As expected, KalSRKO/KO mice showed a decrease in anxiety-like behavior and a passive avoidance deficit. No changes were observed in prepulse inhibition of acoustic startle or tests of depression-like behavior. Growth rate, parturition and pituitary secretion of growth hormone and prolactin were deficient in the KalSRKO/KO mice. Based on the fact that a subset of Kalrn isoforms is expressed in mouse skeletal muscle and the observation that muscle function in C.elegans requires its Kalrn orthologue, KalSRKO/KO mice were evaluated in the rotarod and wire hang tests. KalSRKO/KO mice showed a profound decrease in neuromuscular function, with deficits apparent in KalSR+/KO mice; these deficits were not as marked when loss of Kalrn expression was restricted to the nervous system. Pre- and postsynaptic deficits in the neuromuscular junction were observed, along with alterations in sarcomere length. Conclusions Many of the widespread and diverse deficits observed both within and outside of the nervous system when expression of Kalrn is eliminated may reflect its role in secretory granule function and its expression outside of the nervous system.
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