The heterozygous reeler mouse: behavioural phenotype.

The aim of this study was to investigate whether heterozygous reeler mice (+/rl) could be used as a genetic mouse model of schizophrenia, as previously suggested [J. Med. Chem. 44 (2001) 477]. The behavioural phenotype of male and female +/rl mice (young adult: 50-70 days old, and fully adult: >75 days old) was compared to their wild type (+/+) littermates. A complex behavioural test battery was employed: Irwin test, rotarod, spontaneous locomotor activity, social behaviour, light-dark transition test, startle response and prepulse inhibition, and hot-plate test. Overall, +/rl mice did not differ from their +/+ littermates at either age, although fully adult +/rl male mice spent more time engaged in social investigation. Some of the behavioural measures investigated were influenced by gender. Young female mice were more active in the light/dark transition test than males, while males were more aggressive than females during social interaction. In addition, performance on the rotarod was shown to deteriorate with age. Our data are in agreement with previous findings [Soc. Neurosci. Abst. 27 (2001) 238; J. Psychopharmacol. 17 (2003) A43], but contrary to those of Costa et al. [Curr. Opin. Pharmacol. 2 (2002) 56], although mice used in the present and previous studies were derived from the same genetic stock at Jackson Laboratories, USA. The present study clearly shows that, compared to its +/+ littermates, the +/rl mouse (young/fully adult) exhibits normal behaviour in a wide range of behavioural measures and suggest that these mice may not be suitable for use as a genetic animal model of schizophrenia.

Hippocampal auditory gating in the hyperactive mocha mouse.

The mouse mutants mocha (mh) and mocha2J (mh2J) result from separate mutations in the same gene (AP-3 delta) that arose independently on different backgrounds of inbred strains. They exhibit a neurological phenotype that includes hyperactivity, an epileptiform EEG and changes in the basic function of the hippocampus. Depth electrode recordings of hippocampal auditory evoked potentials revealed that the response to the first of two paired tones was significantly enhanced in mocha and mocha2J, as compared with littermate controls. The pronounced theta rhythm characteristic of unanesthetized mocha mice was not observed in these chloral-hydrate anesthetized mice, whereas spike discharge activity was frequently present in the recordings.

Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami.

Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami. Recent studies of the homozygous tottering (Cacna1atg) and lethargic mouse (Cacnb4(lh)) models of absence seizures have identified mutations in the genes encoding the alpha1A and beta4 subunits, respectively, of voltage-gated Ca2+ channels (VGCCs). beta subunits normally regulate Ca2+ currents via a direct interaction with alpha1 (pore-forming) subunits of VGCCs, and VGCCs are known to play a significant role in controlling the release of transmitter from presynaptic nerve terminals in the CNS. Because the gene mutation in Cacnb4(lh) homozygotes results in loss of the beta4 subunit's binding site for alpha1 subunits, we hypothesized that synaptic transmission would be altered in the CNS of Cacnb4(lh) homozygotes. We tested this hypothesis by using whole cell recordings of single cells in an in vitro slice preparation to investigate synaptic transmission in one of the critical neuronal populations that generate seizure activity in this strain, the somatosensory thalamus. The primary finding reported here is the observation of a significant decrease in glutamatergic synaptic transmission mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA receptors in somatosensory thalamic neurons of Cacnb4(lh) homozygotes compared with matched, nonepileptic mice. In contrast, there was no significant decrease in GABAergic transmission in Cacnb4(lh) homozygotes nor was there any difference in effects mediated by presynaptic GABAB receptors. We found a similar decrease in glutamatergic but not GABAergic responses in Cacna1atg homozygotes, suggesting that the independent mutations in the two strains each affected P/Q channel function by causing defective neurotransmitter release specific to glutamatergic synapses in the somatosensory thalamus. This may be an important factor underlying the generation of seizures in these models.

Course and collaterals of corticospinal fibers arising from the sensorimotor cortex of the reeler mouse.

The reeler genetic mutation, occurring spontaneously in mice, affects migration of neuroblasts in the central nervous system at its last stage, causing severe cytoarchitectonic abnormalities in laminated structures, such as the cerebral and cerebellar cortex. In the reeler mouse, corticospinal (CS) neurons are malpositioned in association with the deranged laminar cytoarchitecture. To examine whether CS projections in the reeler mouse and their collaterals terminating with subcortical nuclei are normal or not, 5% biocytin was injected into the sensorimotor cortex of 2-month-old normal and reeler mice. Anterogradely labeled CS fibers of normal and reeler mice exited from the cortex and entered the internal capsule and the cerebral peduncle. They penetrated the basal pontine gray matter as longitudinal pontine fibers and entered the medullary pyramid. They continued caudally as a compact bundle along the ventral surface of the medulla, passed through the pyramidal decussation at the spinomedullary junction and entered the contralateral dorsal funiculus of the spinal cord. Both in normal and reeler mice, collaterals arising from these CS fibers projected to the ipsilateral red nucleus, basal pontine gray matter, inferior olivary complex, and the contralateral gracile nucleus. Thus, in the reeler mouse, the course and termination of CS fibers and their collaterals are identical to their normal counterparts, suggesting that radially malpositioned CS neurons in the sensorimotor cortex project to the subcortical nuclei in a manner similar to normal CS neurons.

Interactions between growing thalamocortical afferent axons and the neocortical primordium in normal and reeler mutant mice.

The interactions between growing thalamocortical afferent axons and the neocortical primordium were examined during neocortical development of the mouse cerebrum, by labeling the afferents with the carbocyanine fluorescent dye, DiI, which was introduced into the dorsal thalamus of the fixed brains of control and reeler mutant mice. In the neocortical primordium of the control mouse, the labeled afferents running tangentially in the intermediate zone formed a dense plexus in the subplate, the layer below the cortical plate, as early as the 16th gestational day (E16). Small numbers of the afferents invaded the lower cortical plate at E16 and increasing numbers of labeled growing axons extended into the cortical plate at E17. At the 4th postnatal day (P4), labeled afferents grew radially up to the upper cortical plate and terminal arborizations of the afferents were evident in the forming layer IV. In contrast, in the E16 cerebrum of the reeler mutant mouse, in which the cortical layers are inverted, the labeled afferents traversed the neocortical primordium directly towards the superplate, the superficial layer above the cortical plate and the equivalent of the subplate in the control mouse. Thick bundles of labeled axons reached the superplate and made contact with the superplate neurons. At P4 in the reeler neocortex, the afferent axons that had reached the superplate began to change their direction of growth and turned towards the deeper layer. Electron-microscopic observations at E16 revealed that immature synapses were formed on the somata of the subplate neurons in the control mouse, and similar immature synapses were also formed on the superplate neurons of the reeler mutant. At E16 in the control, NGF receptor immunoreactivity was expressed in the intermediate zone, subplate and lower cortical plate, and the mode of expression corresponded to the distribution of thalamocortical afferents. At the same stage of the reeler mutant, expression of NGF receptor immunoreactivity was confined to the afferent axons that had grown through the neocortical primordium towards the superplate. In the control at E17, highly polysialylated NCAM (NCAM-H), a homophilic cell adhesion molecule, was expressed in the subplate, marginal zone and afferent axons. In the reeler mutant at the same stage, this adhesion molecule was expressed in both the superplate and the bundles of the afferent axons. These findings suggest that the subplate and the superplate, which are composed of neurons generated at the earliest stage, attract growing thalamocortical afferent axons specifically by a chemotropic mechanism through the expression of NGF receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

[Dislocated neurons and neural network: hodological study of the motor cortex of the reeler mutant mouse].

Reeler, an autosomal recessive mutation in mice, causes cytoarchitectonic abnormalities of cerebral cortex, which are characterized by malposition of neurons. We examined hodological systems of the reeler motor cortex. The results are described as follows. (1) In normal controls, corticospinal tract neurons retrogradely labeled after the injection of HRP ioto the lumbar cord were situated only in layer V (layer of large pyramids: LP). In the reeler, by contrast, the labeled corticospinal tract neurons were scattered diffusely throughout all levels of the corresponding area. (2) In the normal controls, callosal commissural neurons retrogradely labeled after the HRP injection into the motor cortex were distributed in a bilaminar pattern such that the largest number of cells were located in the supragranular layers II (layer of small pyramids; SP) and III (layer of medium pyramids; MP), and in the infragranular layer V (LP). In the reeler mutant mice, callosal commissural neurons were found in all cortical layers, but two-thirds were situated in the lower half of the cortex. (3) In the normal controls, most of the thalamocortical neurons labeled after HRP injection into the motor cortex were located in the ventrolateral nucleus, the lateral division of the ventrobasal nucleus, the central lateral, paracentral and central intralaminar nuclei, and the medial division of the posterior complex. In the reeler mutant mice, retrogradely labeled neurons were again found in the nuclei referred to above, and the distribution pattern and morphology of HRP-filled neurons were also similar to those of normal controls. In the reeler, thalamocortical fibers took an abnormal course within the motor cortex: they ascended obliquely from the white matter to the pial surface and then descended obliquely to the deeper layers. These results strongly suggest that dislocated neurons project correctly to normally-situated and/or abnormally situated target(s).

The female brindled mouse as a model of Menkes' disease: the relationship of fur pattern to behavioral and neurochemical abnormalities.

The brindled mottled mutant mouse, a model of Menkes' disease, has alterations in copper homeostasis which cause, among other sequelae, neuronal degeneration in selected areas of brain. This work examined the neurochemical changes at postnatal days (PND) 15, 30 and 60 in females heterozygous for the sex-linked brindled mutation. These data were compared to behavioral alterations and to fur coat color at these same time points. The brindled heterozygotic females had lower concentrations of norepinephrine (NE) in the cingulate cortex, and higher levels of dopamine or dopamine metabolites in the cingulate cortex, thalamus and hypothalamus across all ages, although the difference was greatest at PND 15. The brindled females were much less active than their normal littermates at PND 15, but the differences were no longer evident at PND 30 and 60. Mottling of the fur is believed to result from low tyrosinase activity caused by abnormalities in copper metabolism. The fur pattern and behavior of the brindled mice were highly correlated with NE levels in the cingulate cortex and thalamus. These data show that female brindled mice have neurochemical abnormalities similar to (if less severe than) the male hemizygotes, that these abnormalities are regionally specific, are most apparent prior to 30 days of age, and are linked to behavioral deficits. These data also show that the extent of such deficits can be predicted by a quantitative analysis of the fur pattern of these females.