Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome.

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3-4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7-8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

Multicentric plasmacytoma in a harbor porpoise Phocoena phocoena off the coast of Whidbey Island, Washington State, USA.

Necropsy of a female adult pregnant harbor porpoise Phocoena phocoena revealed a multicentric plasmacytoma. The plasmacytoma infiltrated the cranial lung lobes, mediastinal lymph nodes and the spleen. Diagnosis was based on gross, histopathologic and immunohistochemical studies. Histopathology revealed a diffuse proliferation of atypical pleomorphic neoplastic round cells with plasmacytic features. Positive immunohistochemistry with anti-CD79a and anti-CD20 antibody markers and anti-multiple myeloma oncogene 1 (MUM-1) for plasmacytoma confirmed this neoplasm to be of B-cell origin. This is the first recorded case of a plasmacytoma in a harbor porpoise. Routine viral screening was negative via standard PCR for herpesvirus and reverse transcriptase PCR for morbillivirus. Retroviral screening was not performed.

Persistent Organic Pollutant and Hormone Levels in Harbor Porpoise with B Cell Lymphoma.

B-cell lymphoma, a common morphologic variant of non-Hodgkin lymphoma, has been associated with persistent pollutants in humans, but this association is not well-characterized in top-level predators sharing marine resources with humans. We characterized and compared blubber contaminants and hormones of a pregnant harbor porpoise (Phocoena phocoena) with B-cell lymphoma, with those in two presumed healthy fishery by-caught porpoises with no lymphoma: a pregnant adult and female juvenile. Common historic use compounds, including polychlorinated biphenyls, polybrominated diphenyl ethers, and pesticides, were evaluated in blubber samples from three porpoises. In addition, blubber cortisol and progesterone levels (ng/g) were determined in all three animals. Total pollutant concentrations were highest in the juvenile porpoise, followed by the lymphoma porpoise and the nonlymphoma adult. Blubber cortisol concentrations were 191% greater in the pregnant with lymphoma porpoise compared with the pregnant no lymphoma porpoise, and 89% greater in the juvenile female compared with the pregnant no lymphoma porpoise. Although both adults were pregnant, progesterone levels were substantially greater (90%) in the healthy compared with the lymphoma adult. Health monitoring of top-level marine predators, such as porpoise, provides a sentinel measure of contaminants that serve as indicators of potential environmental exposure to humans.

Vaginal calculi in a juvenile harbor porpoise (Phocoena phocoena).

A large number of vaginal calculi were observed in a juvenile harbor porpoise (Phocoena phocoena) stranded on Whidbey Island, Washington. Vaginal calculi have been reported in other species, but not in harbor porpoises. Histologic examination of the urinary tract revealed mucosal hyperplasia most likely attributable to the calculi. The calculi were numerous (>30), composed completely of struvite (magnesium ammonium phosphate), and on culture yielded Enterococcus spp., a bacterium not usually associated with struvite urolith formation in domestic animals. The only other lesion of note was severe hepatic lipidosis, and its relationship to the development of the vaginal calculi is unknown.