Corrigendum: Inhibitory Effect of Codeine on Sucrase Activity.

A typographical error appeared in the author's name of the article entitled "Inhibitory Effect of Codeine on Sucrase Activity" by Dariush Minai-Tehrani, Saeed Minoui, Marzie Sepehre, Zohre Sharif-Khodai, Tooka Aavani, Drug Metabolism Letters, 2009; 3(1): 58-60. [1]. Details of the error and a correction are provided here. The fourth author's name in this article was misspelled. Hence it should be read as "Zohreh Sharifkhodaei" as per the request of the author. We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/93132/article Original: Zohre Sharif-Khodai Corrected: Zohreh Sharifkhodaei.

Hamartoma-like lesions in the mouse retina: an animal model of Pten hamartoma tumour syndrome.

PTEN hamartoma tumour syndrome (PHTS) is a heterogeneous group of rare, autosomal dominant disorders associated with PTEN germline mutations. PHTS patients routinely develop hamartomas, which are benign tissue overgrowths comprised of disorganized 'normal' cells. Efforts to generate PHTS animal models have been largely unsuccessful due to the early lethality of homozygous germline mutations in Pten, together with the lack of hamartoma formation in most conditional mutants generated to date. We report herein a novel PHTS mouse model that reproducibly forms hamartoma-like lesions in the central retina by postnatal day 21. Specifically, we generated a Pten conditional knockout (cKO) using a retinal-specific Pax6::Cre driver that leads to a nearly complete deletion of Pten in the peripheral retina but produces a mosaic of 'wild-type' and Pten cKO cells centrally. Structural defects were only observed in the mosaic central retina, including in Müller glia and in the outer and inner limiting membranes, suggesting that defective mechanical integrity partly underlies the hamartoma-like pathology. Finally, we used this newly developed model to test whether rapamycin, an mTOR inhibitor that is currently the only PHTS therapy, can block hamartoma growth. When administered in the early postnatal period, prior to hamartoma formation, rapamycin reduces hamartoma size, but also induces new morphological abnormalities in the Pten cKO retinal periphery. In contrast, administration of rapamycin after hamartoma initiation fails to reduce lesion size. We have thus generated and used an animal model of retinal PHTS to show that, although current therapies can reduce hamartoma formation, they might also induce new retinal dysmorphologies.This article has an associated First Person interview with the first author of the paper.

Temporal profiling of photoreceptor lineage gene expression during murine retinal development.

Rod and cone photoreceptors are photosensitive cells in the retina that convert light to electrical signals that are transmitted to visual processing centres in the brain. During development, cones and rods are generated from a common pool of multipotent retinal progenitor cells (RPCs) that also give rise to other retinal cell types. Cones and rods differentiate in two distinct waves, peaking in mid-embryogenesis and the early postnatal period, respectively. As RPCs transition from making cones to generating rods, there are changes in the expression profiles of genes involved in photoreceptor cell fate specification and differentiation. To better understand the temporal transition from cone to rod genesis, we assessed the timing of onset and offset of expression of a panel of 11 transcription factors and 7 non-transcription factors known to function in photoreceptor development, examining their expression between embryonic day (E) 12.5 and postnatal day (P) 60. Transcription factor expression in the photoreceptor layer was observed as early as E12.5, beginning with Crx, Otx2, Rorb, Neurod1 and Prdm1 expression, followed at E15.5 with the expression of Thrb, Neurog1, Sall3 and Rxrg expression, and at P0 by Nrl and Nr2e3 expression. Of the non-transcription factors, peanut agglutinin lectin staining and cone arrestin protein were observed as early as E15.5 in the developing outer nuclear layer, while transcripts for the cone opsins Opn1mw and Opn1sw and Recoverin protein were detected in photoreceptors by P0. In contrast, Opn1mw and Opn1sw protein were not observed in cones until P7, when rod-specific Gnat1 transcripts and rhodopsin protein were also detected. We have thus identified four transitory stages during murine retina photoreceptor differentiation marked by the period of onset of expression of new photoreceptor lineage genes. By characterizing these stages, we have clarified the dynamic nature of gene expression during the period when photoreceptor identities are progressively acquired during development.

Establishment of a cone photoreceptor transplantation platform based on a novel cone-GFP reporter mouse line.

We report successful retinal cone enrichment and transplantation using a novel cone-GFP reporter mouse line. Using the putative cone photoreceptor-enriched transcript Coiled-Coil Domain Containing 136 (Ccdc136) GFP-trapped allele, we monitored developmental reporter expression, facilitated the enrichment of cones, and evaluated transplanted GFP-labeled cones in wildtype and retinal degeneration mutant retinas. GFP reporter and endogenous Ccdc136 transcripts exhibit overlapping temporal and spatial expression patterns, both initiated in cone precursors of the embryonic retina and persisting to the adult stage in S and S/M opsin(+) cones as well as rod bipolar cells. The trapped allele does not affect cone function or survival in the adult mutant retina. When comparing the integration of GFP(+) embryonic cones and postnatal Nrl(-/-) 'cods' into retinas of adult wildtype and blind mice, both cell types integrated and exhibited a degree of morphological maturation that was dependent on donor age. These results demonstrate the amenability of the adult retina to cone transplantation using a novel transgenic resource that can advance therapeutic cone transplantation in models of age-related macular degeneration.

Maternal immune activation produces cerebellar hyperplasia and alterations in motor and social behaviors in male and female mice.

There have been suggestions that maternal immune activation is associated with alterations in motor behavior in offspring. To explore this further, we treated pregnant mice with polyinosinic:polycytidylic acid (poly(I:C)), a viral mimetic that activates the innate immune system, or saline on embryonic days 13-15. At postnatal day (P) 18, offspring cerebella were collected from perfused brains and immunostained as whole-mounts for zebrin II. Measurements of zebrin II+/- stripes in both sexes indicated that prenatal poly(I:C)-exposed offspring had significantly wider stripes; this difference was also seen in similarly treated offspring in adulthood (~P120). When sagittal sections of the cerebellum were immunostained for calbindin and Purkinje cell numbers were counted, we observed greater numbers of Purkinje cells in poly(I:C) offspring at both P18 and ~ P120. In adolescence (~P40), both male and female prenatal poly(I:C)-exposed offspring exhibited poorer performance on the rotarod and ladder rung tests; deficits in performance on the latter test persisted into adulthood. Offspring of both sexes from poly(I:C) dams also exhibited impaired social interaction in adolescence, but this difference was no longer apparent in adulthood. Our results suggest that maternal immune exposure at a critical time of cerebellum development can enhance neuronal survival or impair normal programmed cell death of Purkinje cells, with lasting consequences on cerebellar morphology and a variety of motor and non-motor behaviors.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life.

Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopamine-mediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

Compartmentation of the cerebellar cortex in the naked mole-rat (Heterocephalus glaber).

Despite the apparent uniformity in cellular composition of the adult mammalian cerebellar cortex, it is actually highly compartmentalized into transverse zones and within each zone further subdivided into a reproducible array of parasagittal stripes. This basic cerebellar architecture is highly conserved in birds and mammals. However, different species have very different cerebellar morphologies, and it is unclear if cerebellar architecture reflects taxonomic relations or ecological niches. To explore this, we have examined the cerebellum of the naked mole-rat Heterocephalus glaber, a burrowing rodent with adaptations to a subterranean life that include only a rudimentary visual system. The cerebellum of H. glaber resembles that of other rodents with the remarkable exception that cerebellar regions that are prominent in the handling of visual information (the central zone, nodular zone, and dorsal paraflocculus) are greatly reduced or absent. In addition, there is a notable increase in size in the posterior zone, consistent with an expanded role for the trigeminal somatosensory system. These data suggest that cerebellar architecture may be substantially modified to serve a particular ecological niche.

Structural changes and inhibition of sucrase after binding of scopolamine.

Scopolamine (hyoscine) is commonly used as an anticholinergic drug to relieve nausea, vomiting and dizziness of a motion sickness as well as recovery from anesthesia and surgery. Sucrase as a hydrolytic enzyme breaks down sucrose into its monomers, glucose and fructose. The aim of this study was to evaluate the effect of scopolamine on the activity and the structural changes of yeast sucrase. The results showed that binding of scopolamine to sucrase could inhibit the enzyme activity. A non-competitive inhibition was observed in different concentrations of scopolamine (0.6 to 3.6mM). The study by circular dichroism measurement in far-UV showed that the absolute enzyme exhibited a flat negative trough, indicating the presence of alpha-helices and beta-sheet structures in the enzyme. Binding of the inhibitor on the enzyme made a deeper trough at 218nm, suggesting the increasing of beta-sheet content of the enzyme. Fluorescence measurement showed that binding of scopolamine to free enzyme and enzyme-substrate complex increased the peak intensity at 350nm and also induced red shift. Our findings suggest that scopolamine binds to the location other than the active site of enzyme and that the binding causes structural changes and inhibits the enzyme activity.

The locus coeruleus involves in consolidation and memory retrieval, but not in acquisition of inhibitory avoidance learning task.

The locus coeruleus (LC) located at the level of the pons, is involved in cognitive functions such as learning and memory. The bilateral lidocaine-induced reversible inactivation of this nucleus has been considered in order to study its role in the phases of memory processing (acquisition, consolidation and retention) without any interference with the function of the same structure either during earlier and/or later phases of the same process. In this study, inhibitory avoidance (IA) learning task used to find the LC function in acquisition, consolidation and retrieval. Saline or lidocaine 4% (0.5 microl/side) microinjected into the LC, for assessing the acquisition (5 min before training), consolidation (5, 90 and 360 min after training) and memory retrieval, 5 min before testing. The retention test was done 24h after learning. Our results indicated that: (1) The bilateral functional inactivation of LC before training did not affect acquisition, but affected subsequent memory retention 24h later in IA task. (2) The lidocaine-induced inactivation of LC only 5 min after training impaired consolidation but did not affect it after 90 or 360 min. (3) Inactivation of the LC, 5 min before pre-retrieval test, impaired memory retrieval in IA task. In conclusion, it seems that the nucleus locus coeruleus does not affect acquisition while it involves in the memory consolidation and retrieval of inhibitory avoidance learning task.