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

Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease

Active nuclear import and cytoplasmic retention of activation-induced deaminase

The enzyme activation-induced deaminase (AID) triggers antibody diversification in B cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, and its nuclear entry requires active import mediated by a conformational nuclear localization signal. We also identify in its C terminus a determinant for AID cytoplasmic retention, which hampers diffusion to the nucleus, competes with nuclear import and is crucial for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.This work was supported by the Canadian Institutes of Health Research (MOP 84543) and a Canada Research Chair (to J.M.D.). A.O. was supported by a fellowship from the Canadian Institutes of Health Research Cancer Training Program at the IRCM. V.A.C. was supported in part by a Michel Saucier fellowship from the Louis-Pasteur Canadian Fund through the University of Montreal

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0–2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization