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.

  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: A major concern in neuroscience is how cognitive ability in adulthood is affected and regulated by developmental mechanisms. The molecular bases of cognitive development are not well understood. We provide evidence for the involvement of the α2 isoform of Rac-specific guanosine triphosphatase (GTPase)-activating protein (RacGAP) α-chimaerin (chimerin) in this process. We generated and analyzed mice with global and conditional knockouts of α-chimaerin and its isoforms (α1-chimaerin and α2-chimaerin) and found that α-chimaerin plays a wide variety of roles in brain function and that the roles of α1-chimaerin and α2-chimaerin are distinct. Deletion of α2-chimaerin, but not α1-chimaerin, beginning during early development results in an increase in contextual fear learning in adult mice, whereas learning is not altered when α2-chimaerin is deleted only in adulthood. Our findings suggest that α2-chimaerin acts during development to establish normal cognitive ability in adulthood.
    Full-text · Article · Sep 2014 · Cell Reports
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Psychiatric and neurodegenerative disorders, including intellectual disability (ID), autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease (AD), pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance - modulated largely by dopamine - critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan. This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2013 · Journal of Neurochemistry
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2012 · BMC Neuroscience
Show more