Deletion of the STOP gene, a microtubule stabilizing factor, leads only to discrete cerebral metabolic changes in mice

Abstract

In mice, deletion of the STOP protein leads to subtle anatomic changes and induces depleted synaptic vesicle pools, impaired synaptic plasticity, hyperdopaminergy, and major behavioral disorders alleviated by neuroleptics, hence leading to a schizophrenic-like phenotype. In this study, we applied the quantitative autoradiographic [(14)C]2-deoxyglucose technique to study to what extent the basal rate of cerebral glucose utilization in STOP-knockout (STOP-KO) mice occurs in regions where metabolic changes have been reported in schizophrenic patients. Studies were performed on wild-type, heterozygous, and homozygous STOP-KO mice (7-8 per group). Mice were implanted with femoral artery and vein catheters, and cerebral glucose utilization was quantified over 45 min. Compared with that in wild-type mice, glucose utilization in STOP-KO mice was significantly increased in the olfactory cortex, ventromedial and anterolateral hypothalamus, ventral tegmental area, and substantia nigra pars compacta. Nonsignificant increases, ranging between 9% and 19%, were recorded in the whole auditory system, CA1 pyramidal cell layer, and dorsal raphe. Glucose utilization was also significantly increased in heterozygous mice compared with that in wild-type mice in olfactory cortex. These data might reflect hyperdopaminergic activity, olfactory deficits, and sleep disturbances in STOP-KO mice that have also been reported in schizophrenic patients.

Figure 1

Effects of the deletion of the STOP gene on LCMRglcs in heterozygous and homozygous STOP KO mice. Values represent means ± S.D. of 7–8 animals and are expressed as percent of the corresponding level in wild type animals. * p < 0.05, ** p < 0.01, statistically significant differences from levels in wild type mice ° p < 0.05, statistically significant difference from levels in heterozygous mice. Abbreviations: OLFCX: olfactory cortex, ALHYP: anterolateral hypothalamus, VMHYP: ventromedian hypothalamus, VTA: ventral tegmental area, SNPC: substantia nigra, pars compacta, AUDCX: auditory cortex, MGEN: medial geniculate body, ICOL: inferior colliculus, LL: lateral lemniscus, SO: superior olive, CA1: hippocampal CA1 pyramidal cell layer, MFB: median forebrain bundle, DRAP: dorsal raphe, CBCX: cerebellar cortex.

Figure 2

2DG autoradiograms of brain sections of a wild type control (WT) and a STOP KO mouse taken at the level of the midbrain. Compared to the wild type mouse, brain metabolism is increased in the STOP KO mouse at the level of the substantia nigra pars compacta (SNPC), the ventral tegmental area (VTA), the auditory cortex (AUDCX), the CA1 pyramidal cell layer of hippocampus (HIP) and the thalamus (THAL).