Mice Lacking the Immediate Early Gene Egr3 Respond to the Anti-Aggressive Effects of Clozapine Yet are Relatively Resistant to its Sedating Effects

Abstract

Immediate early genes (IEGs) of the early growth response gene (Egr) family are activated in the brain in response to stress, social stimuli, and administration of psycho-active medications. However, little is known about the role of these genes in the biological or behavioral response to these stimuli. Here we show that mice lacking the IEG transcription factor Egr3 (Egr3À/À mice) display increased aggression, and a decreased latency to attack, in response to the stressful social stimulus of a foreign intruder. Together with our findings of persistent and intrusive olfactory-mediated social investigation of conspecifics, these results suggest increased impulsivity in Egr3À/À mice. We also show that the aggression of Egr3À/À mice is significantly inhibited with chronic administration of the antipsychotic medication clozapine. Despite their sensitivity to this therapeutic effect of clozapine, Egr3À/À mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls. This indicates that the therapeutic, anti-aggressive action of clozapine is separable from its sedating activity, and that the biological abnormality resulting from loss of Egr3 distinguishes these different mechanisms. Thus Egr3À/À mice may provide an important tool for elucidating the mechanism of action of clozapine, as well as for understanding the biology underlying aggressive behavior. Notably, schizophrenia patients display a similar decreased susceptibility to the side effects of antipsychotic medications compared to non-psychiatric controls, despite the medications producing a therapeutic response. This suggests the possibility that Egr3À/À mice may provide insight into the neurobiological abnormalities underlying schizophrenia.

Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

“…These parallels indicate that 5-HT2A deficits may play an important role in the behavioral 11,16 and sleep phenotypes demonstrated in Egr3-deficient mice. Yet, there is one key difference between Egr3-/-and 5-HT2A-/-mice in sleep regulation.…”

“…11,16 This effect is shown to be mediated, at least in part, by 5-HT2A receptors, 11 and 5-HT2A receptor-deficient mice display the same phenotype. 17 If Egr3 modulates the expression of plasticity-associated genes and serotonergic signaling in a physiologically relevant manner, it may be essential for waking behavior, sleep timing, and the electroencephalographic manifestations of sleep need.…”

“…These findings are in line with prior studies in Egr3-deficient mice showing resistance to locomotor suppression to similar pharmacological treatment. 11,16 In WT mice, clozapine caused sedation as reported in rats 24 and blockade of the 5-HT2 receptors produced a prolonged inhibition of AW and low-frequency activity. These effects were not detected in Egr3-/-mice.…”

“…Thus, Egr3-/-mice are relatively resistant to the blockade of arousal-promoting mechanisms by clozapine, whether the effect is measured behaviorally, 16 by the timing of wakefulness and sleep, or by electroencephalographic changes during wake.…”

“…18 In the current study, WT and Egr3-/-mice were generated from breeding of Egr3+/-pairs transferred from the colony of Gallitano-Mendel et al 16 where the Egr3 null allele had been backcrossed to C57BL/6 mice more than 20 generations. Egr3-/-mice were identified by polymerase chain reaction genotyping.…”