Oxytocin enhances the inhibitory effects of diazepam in the rat central medial amygdala.

Oxytocin is a neuropeptide that can reduce neophobia and improve social affiliation. In vitro, oxytocin induces a massive release of GABA from neurons in the lateral division of the central amygdala which results in inhibition of a subpopulation of peripherally projecting neurons in the medial division of the central amygdala (CeM). Common anxiolytics, such as diazepam, act as allosteric modulators of GABA(A) receptors. Because oxytocin and diazepam act on GABAergic transmission, it is possible that oxytocin can potentiate the inhibitory effects of diazepam if both exert their pre, - respectively postsynaptic effects on the same inhibitory circuit in the central amygdala. We found that in CeM neurons in which diazepam increased the inhibitory postsynaptic current (IPSC) decay time, TGOT (a specific oxytocin receptor agonist) increased IPSC frequency. Combined application of diazepam and TGOT resulted in generation of IPSCs with increased frequency, decay times as well as amplitudes. While individual saturating concentrations of TGOT and diazepam each decreased spontaneous spiking frequency of CeM neurons to similar extent, co-application of the two was still able to cause a significantly larger decrease. These findings show that oxytocin and diazepam act on different components of the same GABAergic circuit in the central amygdala and that oxytocin can facilitate diazepam effects when used in combination. This raises the possibility that neuropeptides could be clinically used in combination with currently used anxiolytic treatments to improve their therapeutic efficacy.

Islet-brain1/JNK-interacting protein-1 is required for early embryogenesis in mice.

Islet-brain1/JNK-interacting protein-1 (IB1/JIP-1) is a scaffold protein that organizes the JNK, MKK7, and MLK1 to allow signaling specificity. Targeted disruption of the gene MAPK8IP1 encoding IB1/JIP-1 in mice led to embryonic death prior to blastocyst implantation. In culture, no IB1/JIP-1(-/-) embryos were identified indicating that accelerated cell death occurred during the first cell cycles. IB1/JIP-1 expression was detected in unfertilized oocytes, in spermatozoa, and in different stages of embryo development. Thus, despite the maternal and paternal transmission of the IB1/JIP-1 protein, early transcription of the MAPK8IP1 gene is required for the survival of the fertilized oocytes.

The acallosal mouse strain I/LnJ: a putative model of ADHD?

ADHD has been sometimes associated to a defective interhemispheric cross-talk caused by hypoplasia of the corpus callosum. The inbred mouse strain I/LnJ shows total callosal agenesis with complete penetrance, and behavioral features which resemble ADHD. In conditioned learning tasks, as well as in paradigms of spontaneous behavior. I/LnJ mice, as compared to other inbred strains, show lower learning scores, impulsiveness, and significantly higher locomotor activity, albeit with considerable individual variations. In order to disentangle the influences of the genetic background from the effects of the callosal agenesis, we undertook crossing studies between I/LnJ and C57BL/6 mice, obtaining hybrids with missing corpus callosum. In comparison to normal C57BL/6 mice, acallosal hybrids exposed to a novel open-field showed a different locomotor pattern, with less short stops and more center crossing during the beginning of the session. In a metabolic mapping study, the tendency of acallosals to stay off the walls was found to be associated to lower 2-deoxyglucose uptake in the left striatum and cerebral cortex, while the number of short stops was correlated to the bilateral levels of 2-deoxyglucose uptake in the frontal and parietal cortex. The results hint at a right hemisphere dominance in impulsiveness and hyperactivity, boosted by the lack of callosal connections.

Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein.

We previously have reported corpus callosum defects in transgenic mice expressing the beta-amyloid precursor protein (betaAPP) with a deletion of exon 2 and at only 5% of normal levels. This finding indicates a possible involvement of betaAPP in the regulation or guidance of axon growth during neural development. To determine to what degree the betaAPP mutation interacts with genetic background alleles that predispose for forebrain commissure defects in some mouse lines, we have assessed the size of the forebrain commissures in a sample of 298 mice. Lines with mixed genetic background were compared with congenic lines obtained by backcrossing to the parental strains C57BL/6 and 129/SvEv. Mice bearing a null mutation of the betaAPP gene also were included in the analysis. We show that, independently of genetic background, both lack and underexpression of betaAPP are associated with reduced brain weight and reduced size of forebrain commissures, especially of the ventral hippocampal commissure. In addition, both mutations drastically increase the frequency and severity of callosal agenesis and hippocampal commissure defects in mouse lines with 129/SvEv or 129/Ola background.

Increased asymmetries in 2-deoxyglucose uptake in the brain of freely moving congenitally acallosal mice.

To investigate the role of the corpus callosum in the expression of functional brain asymmetries, we compared left and right uptake of [14C]2-deoxyglucose in 43 brain regions measured in 10 C57B1/6 mice with a normal corpus callosum and in 12 congenitally acallosal mice, after 45 min of free activity in a novel, large open-field arena. The metabolic patterns across the brain appeared to be similar in the two groups of mice, as well as the average direction of asymmetry in tracer incorporation, which was higher at right in most of the brain regions for both acallosals and controls. However, the direction of the metabolic asymmetries of any given region was not consistent across individual animals. The largest asymmetries were found in the central auditory nuclei in both groups of mice, with extreme values in some acallosals. Significantly larger asymmetries were found in acallosal mice for the brain and the cortex as a whole, as well as for the lateral geniculate and pretectal nuclei, the olfactory tubercles, and retrosplenial, infrarhinal and perirhinal cortices. The metabolic asymmetries of the thalamic sensory nuclei were correlated with the asymmetries of the corresponding sensory cortical fields in the acallosal, but not in control mice. On the other hand, asymmetries of the cortical regions were largely intercorrelated in control mice, resulting in a general activation of one hemisphere over the other, while in acallosals they were more independent, resulting in a "patchy" pattern of cortical asymmetries. These results suggest that callosal agenesis, combined with the occurrence of ipsilateral Probst bundles, leads to a loss of co-ordination in the activation of different sensory and motor areas. The impaired co-ordination might then be distributed through cortico-subcortical loops, resulting in larger asymmetries throughout the brain. Thus, a normal corpus callosum appears to balance and synchronize metabolic brain activity, perhaps by smoothing the effects of asymmetrically activated ascending systems.