Using Kalirin conditional knockout mice to distinguish its role in dopamine receptor mediated behaviors

Abstract

BackgroundMice lacking Kalirin-7 (Kal7KO), a Rho GDP/GTP exchange factor, self-administer cocaine at a higher rate than wildtype mice, and show an exaggerated locomotor response to experimenter-administered cocaine. Kal7, which localizes to post-synaptic densities at glutamatergic synapses, interacts directly with the GluN2B subunit of the N-methyl-d-aspartate (NMDA; GluN) receptor. Consistent with these observations, Kal7 plays an essential role in NMDA receptor dependent long term potentiation and depression, and glutamatergic transmission plays a key role in the response to chronic cocaine. A number of genetic studies have implicated altered Kalirin expression in schizophrenia and other disorders such as Alzheimer’s Disease.ResultsA comparison of the effects of experimenter-administered cocaine on mice lacking all Kalirin isoforms to its effects on mice lacking only Kalirin-7 identified Kal7 as the key isoform whose deletion produces exaggerated locomotor responses to cocaine. Pretreatment of Kal7KO mice with a low dose of ifenprodil, a selective GluN2B antagonist, eliminated their enhanced locomotor response to cocaine, revealing an important role for GluN2B in this behavior. Selective knockout of Kalirin in dopamine transporter expressing neurons produced a transient enhancement of cocaine-induced locomotion, while knockout of Kalirin in Drd1a- or Drd2-dopamine receptor expressing neurons was without effect. As observed in Kalirin global knockout mice, eliminating Kalirin expression in Drd2-expressing neurons increased exploratory behavior in the elevated zero maze, an effect eliminated by pretreatment with ifenprodil.ConclusionsThe cocaine-sensitive neuronal pathways which are most sensitive to altered Kalirin function may be the pathways most dependent on GluN2B and Drd2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0363-2) contains supplementary material, which is available to authorized users.

The potential therapeutic roles of Rho GTPases in substance dependence

“…Chronic cocaine induced an increased expression of Kal-7 in the NAc of wild-type mice, and overexpression of Kal-7 in cultured MSNs increased the density of dendritic spine, while knocking out of Kal-7 inhibited the increase in spine density after cocaine treatment, indicating that Kal-7 was supposed to be indispensable for increases of dendritic spine density induced by cocaine (Kiraly et al, 2010;Ma et al, 2012). Lack of Kal-7 did not influence acute locomotor response to cocaine, but it could increase cocaine locomotor sensitization and self-administration (Kiraly et al, 2010(Kiraly et al, , 2013LaRese et al, 2017). After 2 weeks withdrawal from repeated cocaine injections, the levels Kal-7 and the activation of its downstream effectors such as Rac1 and PAK in the NAc were increased, while the surface expression of glutamate receptor AMPAR and spine density also increased (Wang et al, 2013).…”

“…Kal-7 knockdown eliminated the increased expression of AMPAR and spine density, and Kal-7 knockdown rats also exhibited locomotor sensitization, however, incentive sensitization, which was assessed by the speed rats learned to self-administer a threshold dose of cocaine, was impaired severely ( Wang et al, 2013 ). Blockade of NR2B with ifenprodil also inhibited locomotor hypersensitization of cocaine in Kal-7 KO mice ( LaRese et al, 2017 ). These results indicated that Kal-7/Rac1/PAK pathway coordinated glutamate receptors to increase dendritic spine density during cocaine withdrawal, while incentive sensitization and locomotor sensitization may involve divergent mechanisms.…”

The Mammalian Kalrn Locus Gives Rise to Several Novel Long Non-coding RNAs

“…Kal7 knockout also resulted in schizophrenia-like effects in adolescent mice (LaRese et al 2017). The Kal7 isoform includes the RacGEF domain but not the RhoGEF domain.…”

A Novel Cis-Regulatory lncRNA, Kalnc2, Downregulates Kalrn Protein-Coding Transcripts in Mouse Neuronal Cells

“…The transcript isoforms can be clustered into two major groups: One group of relatively short isoforms, mostly including the exons at the 5′ end, includes the Kal7 isoform that has been studied extensively in mice and cell culture models. Kal7 knockout also resulted in schizophrenia-like effects in adolescent mice [ 15 ]. The Kal7 isoform includes the RacGEF domain but not the RhoGEF domain.…”