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

ABSTRACT: BACKGROUND:Mice 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. RESULTS:A 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. CONCLUSIONS:The cocaine-sensitive neuronal pathways which are most sensitive to altered Kalirin function may be the pathways most dependent on GluN2B and Drd2.

SUBMITTER: LaRese TP

PROVIDER: S-EPMC5442696 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

LaRese Taylor P TP Yan Yan Y Eipper Betty A BA Mains Richard E RE

BMC neuroscience 20170523 1

<h4>Background</h4>Mice lacking Kalirin-7 (Kal7<sup>KO</sup>), 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 lo ...[more]

PMID: 28535798

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Project description:DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Functional alterations of the basal ganglia circuits have been implicated in this disease. Striatal dopamine receptor 2 (D2R) levels are significantly decreased in DYT1 dystonia patients and in the animal models of DYT1 dystonia. D2R-expressing cells, such as the medium spiny neurons in the indirect pathway, striatal cholinergic interneurons, and dopaminergic neurons in the basal ganglia circuits, contribute to motor performance. However, the function of torsinA in these neurons and its contribution to the motor symptoms is not clear. Here, D2R-expressing-cell-specific Dyt1 conditional knockout (d2KO) mice were generated and in vivo effects of torsinA loss in the corresponding cells were examined. The Dyt1 d2KO mice showed significant reductions of striatal torsinA, acetylcholine metabolic enzymes, Tropomyosin receptor kinase A (TrkA), and cholinergic interneurons. The Dyt1 d2KO mice also showed significant reductions of striatal D2R dimers and tyrosine hydroxylase without significant alteration in striatal monoamine contents or the number of dopaminergic neurons in the substantia nigra. The Dyt1 d2KO male mice showed motor deficits in the accelerated rotarod and beam-walking tests without overt dystonic symptoms. Moreover, the Dyt1 d2KO male mice showed significant correlations between striatal monoamines and locomotion. The results suggest that torsinA in the D2R-expressing cells play a critical role in the development or survival of the striatal cholinergic interneurons, expression of striatal D2R mature form, and motor performance. Medical interventions to compensate for the loss of torsinA function in these neurons may affect the onset and symptoms of this disease.

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

Publications

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

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