The hyperactive syndrome: metanalysis of genetic alterations, pharmacological treatments and brain lesions which increase locomotor activity.

The large number of transgenic mice realized thus far with different purposes allows addressing new questions, such as which animals, over the entire set of transgenic animals, show a specific behavioural abnormality. In the present study, we have used a metanalytical approach to organize a database of genetic modifications, brain lesions and pharmacological interventions that increase locomotor activity in animal models. To further understand the resulting data set, we have organized a second database of the alterations (genetic, pharmacological or brain lesions) that reduce locomotor activity. Using this approach, we estimated that 1.56% of the genes in the genome yield to hyperactivity and 0.75% of genes produce hypoactivity when altered. These genes have been classified into genes for neurotransmitter systems, hormonal, metabolic systems, ion channels, structural proteins, transcription factors, second messengers and growth factors. Finally, two additional classes included animals with neurodegeneration and inner ear abnormalities. The analysis of the database revealed several unexpected findings. First, the genes that, when mutated, induce hyperactive behaviour do not pertain to a single neurotransmitter system. In fact, alterations in most neurotransmitter systems can give rise to a hyperactive phenotype. In contrast, fewer changes can decrease locomotor activity. Specifically, genetic and pharmacological alterations that enhance the dopamine, orexin, histamine, cannabinoids systems or that antagonize the cholinergic system induce an increase in locomotor activity. Similarly, imbalances in the two main neurotransmitters of the nervous system, GABA and glutamate usually result in hyperactive behaviour. It is remarkable that no genetic alterations pertaining to the GABA system have been reported to reduce locomotor behaviour. Other neurotransmitters, such as norepinephrine and serotonin, have a more complex influence. For instance, a decrease in norepinephrine synthesis usually results in hypoactive behaviour. However, a chronic increase in norepinephrine may result in hypoactivity too. Similarly, changes in both directions of serotonin levels may reduce locomotor activity, whereas alterations in specific serotonin receptors can induce hyperactivity. The lesion of at least 12 different brain regions can increase locomotor activity too. Comparatively, few focal lesions decrease locomotor activity. Finally, a large number of toxic events can increase locomotor activity, particularly if delivered during the prepuberal time window. These data show that there is a net imbalance in the number of altered genes/brain lesions/toxics that induce hyperactivity versus hypoactive behaviour. Although some of these data may be explained in terms of the activating role of subcortical systems (such as catecholamines), the larger number of alterations that induce hyperactivity suggests a different scenario. Specifically, we hypothesize (i) the existence of a control system that continuously inhibit a basally hyperactive locomotor tone and (ii) that this control system is highly vulnerable (intrinsic fragility) to any change in the genetic asset or to any toxic/drug delivered during prepuberal stages. Brain lesion studies suggest that the putative control system is located along an axis that connects the olfactory bulb and the enthorhinal cortex (enthorhinal-hippocampal-septal-prefrontal cortex-olfactory bulb axis). We suggest that the increased locomotor activity in many psychiatric diseases may derive from the interference with the development of this brain axis during a specific postnatal time window.