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.
Highlights
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
Using stimulation protocols that can activate N-methyl-d-aspartate receptor (GluN) receptor-independent long-term potentiation (LTP) [21, 22], these data were questioned; detailed analyses demonstrated that GluN receptor-independent LTP was normal in Kalirin-7 knockout (Kal7KO) mice while GluN receptor-dependent LTP was dramatically impaired [11]
When Kalirin spectrin-repeat [total Kalirin] knockout (KalSRKO) mice were tested against wild type (WT) mice using the same paradigm of experimenter-administered cocaine (Fig. 1c), increased locomotor sensitization to cocaine was observed
Summary
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. Using stimulation protocols that can activate GluN receptor-independent LTP [21, 22], these data were questioned; detailed analyses demonstrated that GluN receptor-independent LTP was normal in Kal7KO mice while GluN receptor-dependent LTP was dramatically impaired [11] These findings have been confirmed in studies of spinal cord pain perception, which demonstrated that K al7KO mice lose nociceptordependent LTP, with corresponding blunting of nocifensive behavior (avoiding pain), compared to wildtype mice [23]. Mice injected in the spinal cord with siRNA targeting Kalirin had depressed allodynia [24] Extending these findings, intracellular injection of a Kal7-specific interfering peptide (for which there is no Trio counterpart) totally blocked spinal pain LTP [23], and pharmacologic blockade of Kalirin and Trio guanine nucleotide exchange factor 1 (GEF1) eliminated both long-term potentiation and long-term depression in hippocampal slices [11].
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