Okada, N. J. | bioRxiv Science

bioRxiv2019

Sex and pubertal status influence dendritic spine density onto frontal cortiocostriatal projection neurons

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends late into adolescence. This protracted maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how different cell types in the frontal cortex mature or whether puberty plays a role. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project to the dorsomedial striatum (DMS). We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in males.

neuroscience↗

bioRxiv2018

Anti-NMDA receptor encephalitis in mice induced by active immunization with conformationally-stabilized holoreceptors

Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of antibodies to NMDA receptors in limbic encephalitis, characterized by cognitive changes, memory loss, seizures and sometimes long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights, but does not produce the full spectrum of the human disease. Here we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immune competent mice with conformationally-stabilized, native-like NMDA receptors induced a fulminant encephalitis that was strikingly similar to the behavioral and pathologic characteristics of human cases. Our results provide evidence of neuroinflammation and immune cell infiltration as early and robust features of the autoimmune response. Use of transgenic mice indicated that mature T cells as well as antibody-producing cells were required for disease induction. Our results provide new insights into disease pathogenesis as well as a platform for testing mechanisms of disease initiation and therapeutic approaches.\n\nOne Sentence SummaryWe report an active immunization model of anti-NMDA receptor encephalitis in mice that recapitulates the features of the clinical disease, provides new insights into the pathophysiology, and offers a platform for investigation of new therapeutic interventions.

neuroscience↗