Dynamic Changes in Neurexins' Alternative Splicing: Role of Rho-Associated Protein Kinases and Relevance to Memory Formation

The three neurexins genes (NRXN1/2/3) encode polymorphic synaptic membrane proteins that are involved in cognitive functioning. Neurexins' selectivity of function is presumably conferred through differential use of 2 promoters and 5 alternative splicing sites (SS#1/2/3/4/5). In day-old rat brain neurons grown in culture, activation (depolarization) induces reversible, calcium dependent, repression of NRXN2α SS#3 insert. The effects of depolarization on NRXN1/2/3α splicing and biochemical pathways mediating them were further studied in these neurons. NRXN1/2/3α splicing in the course of memory formation in vivo was also explored, using fear conditioning paradigm in rats in which the animals were trained to associate an aversive stimulus (electrical shock) with a neutral context (a tone), resulting in the expression of fear responses to the neutral context

Mapping alterations to the endogenous elemental distribution within the lateral ventricles and choroid plexus in brain disorders using X-ray fluorescence imaging

The choroid plexus and cerebral ventricles are critical structures for the production of cerebral spinal fluid (CSF) and play an important role in regulating ion and metal transport in the brain, however many aspects of its roles in normal physiology and disease states, such as psychiatric illness, remain unknown. The choroid plexus is difficult to examine in vivo, and in situ ex vivo, and as such has typically been examined indirectly with radiolabeled tracers or ex vivo stains, making measurements of the endogenous K+, Cl-, and Ca+ distributions unreliable. In the present study, we directly examined the distribution of endogenous ions and biologically relevant transition metals in the choroid plexus and regions surrounding the ventricles (ventricle wall, cortex, corpus callosum, striatum) using X-ray fluorescence imaging (XFI). We find that the choroid plexus was rich in Cl- and Fe while K+ levels increase further from the ventricle as Cl- levels decrease, consistent with the known role of ion transporters in the choroid plexus CSF production. A polyI:C offspring displayed enlarged ventricles, elevated Cl- surrounding the ventricles, and intraventricular calcifications. These observations fit with clinical findings in patients with schizophrenia and suggest maternal treatment with polyI:C may lead to dysfunctional ion regulation in offspring. This study demonstrates the power of XFI for examining the endogenous elemental distributions of the ventricular system in healthy brain tissue as well as disease models

The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPβ during epithelial tumour progression

The CCAAT/enhancer binding protein (C/EBP) family of transcription factors is involved in metabolism and differentiation of cells, especially in rodent liver cells and adipocytes. Their roles in vivo and in particular during pathophysiological conditions in humans are largely unknown. We have investigated the presence of C/EBPα, -β, -δ and -ζ in normal ovaries and in epithelial ovarian tumours of different stages. Immunohistochemical experiments demonstrated that C/EBPα and C/EBPβ were preferentially expressed in epithelial/tumour cells irrespective of stage or grade of the tumour. C/EBPβ was located in the nuclei of the cells, in contrast to C/EBPα, which was present only in the cytoplasm of these cells. The nuclear localization of C/EBPβ indicates an active role of this transcription factor in tumour cells, whereas the cytoplasmic distribution suggests a more passive function of C/EBPα. C/EBPδ and -ζ demonstrated a more diverse distribution with predominant localization to epithelial cells, but stromal distribution was also noted. The intracellular distribution was confined to both the nucleus and the cytoplasm for C/EBPδ and -ζ. Western blotting demonstrated that C/EBPα, -β, -δ and -ζ were present in a majority of the samples. The amount of C/EBPβ increased markedly with malignancy, i.e. with degree of dedifferentiation, while the other members of the C/EBP family displayed a more constant expression level. These results demonstrate an association between the expression of members of the C/EBP family and the formation of epithelial ovarian tumours, with C/EBPβ as a potential marker for these tumours. As C/EBPβ is known to be expressed during proliferation of cells in vitro, it may participate in the proliferative process of ovarian epithelial tumour cells in vivo and play a central role in tumour progression. © 1999 Cancer Research Campaig

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

© The Author(s) 2016. Maternal infection during pregnancy increases the risk of offspring developing schizophrenia later in life. Similarly, animal models of maternal immune activation (MIA) induce behavioural and anatomical disturbances consistent with a schizophrenia-like phenotype in offspring. Notably, cognitive impairments in tasks dependent on the prefrontal cortex (PFC) are observed in humans with schizophrenia and in offspring after MIA during pregnancy. Recent studies of post-mortem tissue from individuals with schizophrenia revealed deficits in extracellular matrix structures called perineuronal nets (PNNs), particularly in PFC. Given these findings, we examined PNNs over the course of development in a well-characterized rat model of MIA using polyinosinic-polycytidylic acid (polyI:C). We found selective reductions of PNNs in the PFC of polyI:C offspring which did not manifest until early adulthood. These deficits were not associated with changes in parvalbumin cell density, but a decrease in the percentage of parvalbumin cells surrounded by a PNN. Developmental expression of PNNs was also significantly altered in the amygdala of polyI:C offspring. Our results indicate MIA causes region specific developmental abnormalities in PNNs in the PFC of offspring. These findings confirm the polyI:C model replicates neuropathological alterations associated with schizophrenia and may identify novel mechanisms for cognitive and emotional dysfunction in the disorder