Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice

Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5^?/?) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5^+/+) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5^?/? mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5^?/? mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5^?/? mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes.     

Tactile stimulation-induced rapid elevation of the synaptophysin mRNA expression level in rat somatosensory cortex

Synaptophysin is an integral membrane protein abundant in the synaptic vesicle and is found in nerve terminals throughout the brain. It was recently suggested that synaptophysin is also involved in the modulation of activity-dependent synapse formation. In this study, we examined at the individual level whether tactile stimulation selectively influenced the synaptophysin mRNA expression level in the somatosensory cortex of rats. Anesthetized rats were caressed on the back by an experimenter's palms for 20 min and the mRNA expression levels in the somatosensory and the visual cortices 5 min afterwards were determined using quantitative PCR methodology. The synaptophysin mRNA expression level was selectively higher in the experimental group than in the control group in the somatosensory cortex but not in the visual cortex. This suggests that the mRNA expression level of synaptophysin induced by neuronal activity is related to the regulation of synapse formation or remodeling or both.     

Optical imaging of nociception in primary somatosensory cortex of non-human primates

While the activation of primary somatosensory (SI) cortex during pain perception is consistently reported in functional imaging studies on normal subjects and chronic pain patients, the specific roles of SI, particularly the subregions within SI, in the processing of sensory aspects of pain are still largely unknown. Using optical imaging of intrinsic signal (OIS) and single unit electrophysiology, we studied cortical activation patterns within SI cortex (among Brodmann areas 3a, 3b and 1) and signal amplitude changes to various intensities of non-nociceptive, thermal nociceptive and mechanical nociceptive stimulation of individual distal finerpads in anesthetized squirrel monkeys. We have demonstrated that areas 3a and 1 are preferentially involved in the processing of nociceptive information while areas 3b and 1 are preferentially activated in the processing of non-nociceptive (touch) information. Nociceptive activations of individual fingerpad were organized topographically suggesting that nociceptive topographic map exits in areas 3a and 1. Signal amplitude was enhanced to increasing intensity of mechanical nociceptive stimuli in areas 3a, 3b and 1. Within area 1, nociceptive response co-localizes with the non-nociceptive response. Therefore, we hypothesize that nocicepitve information is area-specifically represented within SI cortex, in which nociceptive inputs are preferentially represented in areas 3a and 1 while non-nociceptive inputs are preferentially represented in areas 3b and 1.     

NR2A but not NR2B N-methyl-D-aspartate receptor subunit is altered in the visual cortex of BDNF-knock-out mice

1. Aim of the present paper is to study the expression of N-Methyl-D-Aspartate receptor (NMDAR) subunits NR2A and NR2B within mouse visual cortex.2. To investigate the influence of neurotrophic factor of NGF family (neurotrophins) on NMDAR expression we used mutant mice carrying a deletion in the gene for brain-derived neurotrophic factor (BDNF), a well-known neurotrophin expressed in visual cortex.3. Western blot and immunohistochemistry were performed at postnatal day P12–14, P21–23, and adulthood showing that both subunits change during postnatal development.4. Absence of BDNF induced a reduction of NR2A level. This effect was specific since the other subunit investigated, NR2B, was not affected in mutant mice.5. We conclude that endogenous BDNF modulates NMDAR expression in the developing visual cortex.     

Neural response to movement of the hand and mouth in the secondary somatosensory cortex of Japanese monkeys during a simple feeding task

Abstract

Neural activity was recorded in the secondary somatosensory cortex (SII) of macaque monkeys during a simple feeding task. Around the border between the representations of the hand and face in SII, we found neurons that became active during both retrieving with the hand and eating; 59% had receptive fields (RFs) in the hand/face and the remaining 41% had no RFs. Neurons that responded to touching objects were rarely found. This suggests their sensorimotor function rather than tactile object recognition.     

Glutaminase in the postnatally developing rat cerebellum: Comparison of staining and immunocytochemistry activity

Distribution patterns and developmental profiles of phosphate activated glutaminase (PAG) in the cerebellar cortex of the rat were demonstrated by enzyme activity staining (tetrazolium salt technique) and immunolabeling. Histochemical evaluation of enzyme activity stained sections revealed in the molecular and granular layer (i.e. premigratory zone and external germinal zone in neonate rats) an increase from postnatal day 2 to day 50 by 350 and 400%, respectively. The smallest elevation was found in Purkinje cell bodies (140%). Maximum rise of PAG-activity was observed for all of the areas examined between day 12 and 15. The immunocytochemical visualisation of PAG-like immunoreactivity resulted in spatial and developmental patterns which differed from those of PAG-activity staining and displayed, to some extent, dependency on the way of tissue preparation, especially the fixation procedure.     

Cell-type-specific recruitment of GABAergic interneurons in the primary somatosensory cortex by long-range inputs

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Emergence of layer IV barrel cytoarchitecture is delayed in somatosensory cortex of GAP-43 deficient mice following delayed development of dendritic asymmetry

The emergence of barrel cytoarchitecture in mouse somatosensory cortex is extremely well defined. However, mechanisms underlying the development of this cellular organization are not completely understood. While it is generally accepted that hollows emerge via passive displacement of cortical cells by dense thalamocortical afferent clusters in barrel centers, it is not known what causes cellular segregation of barrel sides and septa. Here, we hypothesized that the emergence of sides and septa is related to the progressive asymmetry of dendrites from the cells of the barrel side toward the barrel hollow during development. We tested this hypothesis in the barrel cortex of growth-associated protein-43 heterozygous mice (GAP43 (+/?) mice) that display a 2-day delay in retraction of septally oriented dendrites compared to (+/+) littermates. We predicted that this delayed retraction would result in a subsequent 2-day delay in the emergence of barrel sides and septa. Using cresyl violet staining of barrel cortex, we found that initial emergence of hollows was not different between GAP43 (+/?) mice and (+/+) littermate controls. However, the emergence of sides and septa was delayed by 2 days, supporting our hypothesis that the emergence of barrel sides and septa is related to, and perhaps reliant upon, the developmental step of dendritic orientation toward barrel hollows. This process, which is mechanistically distinct from the emergence of barrel hollows, is likely due to both active and passive events resulting from asymmetric cell orientation.     

Lamination of the cerebral cortex is disturbed in Gli3 mutant mice

The layered organization of the cerebral cortex develops in an inside-out pattern, a process which is controlled by the secreted protein reelin. Here we report on cortical lamination in the Gli3 hypomorphic mouse mutant Xt^J/Pdn which lacks the cortical hem, a major source of reelin⁺ Cajal Retzius cells in the cerebral cortex. Unlike other previously described mouse mutants with hem defects, cortical lamination is disturbed in Xt^J/Pdn animals. Surprisingly, these layering defects occur in the presence of reelin⁺ cells which are probably derived from an expanded Dbx1⁺ progenitor pool in the mutant. However, while these reelin⁺ neurons and also Calretinin⁺ cells are initially evenly distributed over the cortical surface they form clusters later during development suggesting a novel role for Gli3 in maintaining the proper arrangement of these cells in the marginal zone. Moreover, the radial glial network is disturbed in the regions of these clusters. In addition, the differentiation of subplate cells is affected which serve as a framework for developing a properly laminated cortex.     

Sexual differences in the numerical density of synaptic profiles of developing rat visual cortex

Axo-dendritic synaptic profiles were quantified along the whole depth of the visual cortex of 10-day-old male and female rats. In both sexes the numerical density of synaptic profiles on spine-like structures was greater than the numerical density of synapses on dendritic shafts. Females had a significantly greater numerical density of synaptic profiles on spine-like structures, than did males at a distance of 200–400 and 500–600 μm from the pia surface, which corresponds to layers II–III and IV of the cortex, respectively. A small percentage (2%–4%) of spine-like structures received two presynaptic terminals. This type of double synapses was three times more abundant in females. No sex differences were found in the numerical density of synapses on dendritic shafts in any cortical layer. 1994 John Wiley & Sons, Inc.     

Bimodal septal and cortical triggering and complex propagation patterns of spontaneous waves of activity in the developing mouse cerebral cortex

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18‐P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA_A and AMPA receptors are involved in spontaneous activity. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 679–692, 2010     

Roles of glutamate and GABA receptors in setting the developmental timing of spontaneous synchronized activity in the developing mouse cortex

Spontaneous, synchronized electrical activity (SSA) plays important roles in nervous system development, but it is not clear what causes it to start and stop at the appropriate times. In previous work, we showed that when SSA in neonatal mouse cortex is blocked by TTX in cultured slices during its normal time of occurrence (E17-P3), it fails to stop at P3 as it does in control cultured slices, but instead persists through at least P10. This indicates that SSA is self-extinguishing. Here we use whole-cell recordings and [Ca2+]i imaging to compare control and TTX-treated slices to isolate the factors that normally extinguish SSA on schedule. In TTX-treated slices, SSA bursts average 4 s in duration, and have two components. The first, lasting about 1 s, is mediated by AMPA receptors; the second, which extends the burst to 4 s and is responsible for most of the action potential generation during the burst, is mediated by NMDA receptors. In later stage (P5-P9) control slices, after SSA has declined to about 4% of its peak frequency, bursts lack this long NMDA component. Blocking this NMDA component in P5-P9 TTX-treated slices reduces SSA frequency, but not to the low values found in control slices, implying that additional factors help extinguish SSA. GABA(A) inhibitors restore SSA in control slices, indicating that the emergence of GABA(A)-mediated inhibition is another major factor that helps terminate SSA.     

A molecular marker confirms that the rate of adult maturation is largely independent of the rate of pre-adult development in Drosophila melanogaster

The separation of adult from pre-adult life seen with animals such as Drosophila melanogaster, which are holometabolous and undergo complete metamorphosis, provides the opportunity to examine the contribution of pre-adult rate of development on the rate of maturation and aging of the adult. Recent work has shown that when ambient temperature is used to alter the rate of development there is little effect on adult life span. From this work it has been concluded that the rate of aging is largely independent of the rate of pre-adult development. However, the techniques used to examine life span did not allow for the examination of the earliest events of adult life. Our experimental design used a molecular marker linked to life span as a sensitive measure of determining physiological age. In this way, we were able to evaluate the effect of pre-adult rate of development on the earliest events of adult life. Using ambient temperature to alter both the rate of development in the pre-adult and the rate of aging in the adult independently, we were able to show that it is the ambient temperature at which the adults are living that is the principle determinant of the rate of maturation and aging of the adult. Little effect was seen on the rate of adult maturation in response to an acceleration or a slowing down of the rate of pre-adult development as measured by our molecular marker. These data support the conclusions drawn by others who examined the effect of the rate of development on adult life expectancy. The timing mechanisms at work during pre-adult and adult life appear to be largely regulated separately. If there is such a thing as a physiological clock, it appears to be reset upon eclosion. © 1996 Wiley-Liss, Inc.     

Interleukin-6 is a better marker of lethality than tumor necrosis factor in endotoxin treated mice

Abstract We established a mouse model to differentiate between a lethal and non-lethal presentation of endotoxic shock. The model involved injecting different amounts of Escherichia coli LPS into C3H/HeN mice which had been 'primed' with BCG. We found that the mice receiving non-lethal and lethal doses of LPS could not be differentiated in terms of their physical symptoms for the first 8 h post-injection. Tumour necrosis factor (TNF) was detected at concentrations 2–9-fold greater in mice receiving lethal doses of LPA when compared with non-lethally injected mice. However, given that (i) the successful detection of this differential was dependent on the time of sampling and (ii) that TNF was only detected in the first 3–4 h post LPS challenge, we suggest that TNF may not be very useful as a prognostic marker in endotoxic shock. In contrast, circulating IL-6 appeared to mirror the symptoms of the endotoxic mice. The relative disappearance of IL-6 after 10 h in the non-lethally injected mice corresponded with their symptomatic recovery, while IL-6 continued to circulate up to the time of death in the lethally injected mice. Furthermore, there appeared to be a good correlation between the levels of injected LPS and the levels of IL-6 induced into the circulation. Our results suggest that IL-6, rather than TNF, may serve as a prognostic marker for endotoxic shock.