AUTS2 Regulates RNA Metabolism and Dentate Gyrus Development in Mice.

Human AUTS2 mutations are linked to a syndrome of intellectual disability, autistic features, epilepsy, and other neurological and somatic disorders. Although it is known that this unique gene is highly expressed in developing cerebral cortex, the molecular and developmental functions of AUTS2 protein remain unclear. Using proteomics methods to identify AUTS2 binding partners in neonatal mouse cerebral cortex, we found that AUTS2 associates with multiple proteins that regulate RNA transcription, splicing, localization, and stability. Furthermore, AUTS2-containing protein complexes isolated from cortical tissue bound specific RNA transcripts in RNA immunoprecipitation and sequencing assays. Deletion of all major functional isoforms of AUTS2 (full-length and C-terminal) by conditional excision of exon 15 caused breathing abnormalities and neonatal lethality when Auts2 was inactivated throughout the developing brain. Mice with limited inactivation of Auts2 in cerebral cortex survived but displayed abnormalities of cerebral cortex structure and function, including dentate gyrus hypoplasia with agenesis of hilar mossy neurons, and abnormal spiking activity on EEG. Also, RNA transcripts that normally associate with AUTS2 were dysregulated in mutant mice. Together, these findings indicate that AUTS2 regulates RNA metabolism and is essential for development of cerebral cortex, as well as subcortical breathing centers.

Perinatal Breathing Patterns and Survival in Mice Born Prematurely and at Term.

Infants born prematurely, often associated with maternal infection, frequently exhibit breathing instabilities that require resuscitation. We hypothesized that breathing patterns during the first hour of life would be predictive of survival in an animal model of prematurity. Using plethysmography, we measured breathing patterns during the first hour after birth in mice born at term (Term 19.5), delivered prematurely on gestational day 18.5 following administration of low-dose lipopolysaccharide (LPS; 0.14 mg/kg) to pregnant dams (LPS 18.5), or delivered on gestational day 18.7 or 17.5 by caesarian section (C-S 18.5 and C-S 17.5, respectively). Our experimental approach allowed us to dissociate effects caused by inflammation, from effects due to premature birth in the absence of an inflammatory response. C-S 17.5 mice did not survive, whereas mortality was not increased in C-S 18.5 mice. However, in premature pups born at the same gestational age (day 18.5) in response to maternal LPS injection, mortality was significantly increased. Overall, mice that survived had higher birth weights and showed eupneic or gasping activity that was able to transition to normal breathing. Some mice also exhibited a "saw tooth" breathing pattern that was able to transition into eupnea during the first hour of life. In contrast, mice that did not survive showed distinct, large amplitude, long-lasting breaths that occurred at low frequency and did not transition into eupnea. This breathing pattern was only observed during the first hour of life and was more prevalent in LPS 18.5 and C-S 18.5 mice. Indeed, breath tidal volumes were higher in inflammation-induced premature pups than in pups delivered via C-section at equivalent gestational ages, whereas breathing frequencies were low in both LPS-induced and C-section-induced premature pups. We conclude that a breathing pattern characterized by low frequency and large tidal volume is a predictor for the failure to survive, and that these characteristics are more often seen when prematurity occurs in the context of maternal inflammation. Further insights into the mechanisms that generate these breathing patterns and how they transition to normal breathing may facilitate development of novel strategies to manage premature birth in humans.

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system.

Mammals must continuously regulate the levels of O2 and CO2 , which is particularly important for the brain. Failure to maintain adequate O2 /CO2 homeostasis has been associated with numerous disorders including sleep apnoea, Rett syndrome and sudden infant death syndrome. But, O2 /CO2 homeostasis poses major regulatory challenges, even in the healthy brain. Neuronal activities change in a differentiated, spatially and temporally complex manner, which is reflected in equally complex changes in O2 demand. This raises important questions: is oxygen sensing an emergent property, locally generated within all active neuronal networks, and/or the property of specialized O2 -sensitive CNS regions? Increasing evidence suggests that the regulation of the brain's redox state involves properties that are intrinsic to many networks, but that specialized regions in the brainstem orchestrate the integrated control of respiratory and cardiovascular functions. Although the levels of O2 in arterial blood and the CNS are very different, neuro-glial interactions and purinergic signalling are critical for both peripheral and CNS chemosensation. Indeed, the specificity of neuroglial interactions seems to determine the differential responses to O2 , CO2 and the changes in pH.

Inner ear lesion and the differential roles of hypoxia and hypercarbia in triggering active movements: Potential implication for the Sudden Infant Death Syndrome.

Infants that succumb to Sudden Infant Death Syndrome (SIDS) have been identified with inner ear dysfunction (IED) at birth and on autopsy. We previously investigated whether IED could play a mechanistic role in SIDS. We discovered that animals with IED displayed significant suppression of movement arousal to a hypoxic-hypercarbic gas mixture under light anesthesia. In the current study we investigated the role of each gas in triggering movements and the response to hypercarbia during natural sleep without anesthesia. Seventeen-day-old CD-1 mice received intra-tympanic gentamicin (IT-Gent) injections to precipitate IED. The movement response to hypercarbia, hypoxia and hypoxia-hypercarbia was compared to controls under light anesthesia. Hypercarbia did not stimulate vigorous movements in any animals under either sleep condition. Hypoxia triggered vigorous movements in controls (p<0.05) and a decreased response in IT-Gent animals under light anesthesia. This contrasted with combined hypoxia-hypercarbia, in which IT-Gent animals displaced significantly suppressed movements compared to controls (p<0.05). Our findings portray that a degree of intact inner ear function is necessary for instigating the movement response. Additionally, hypoxia is the trigger for the movement response while carbon dioxide (CO2) suppresses it. The finding that carbon dioxide did not stimulate movement during natural sleep is an important finding. This contrasts with other studies that have identified hypercarbia as an arousal stimulus with EEG. Further studies are warranted to evaluate the precise role of the inner ear in the movement response and potential association with SIDS. The early detection of IED in SIDS predisposed cases could be invaluable.