Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.National Institute of Mental Health (U.S.) (NIMH/NIH (R01MH081201))Hartwell Foundation (Hartwell Individual Biomedical Research Award)Simons Foundation (Autism Research Initiative (SFARI) grant Award)Brain and Behavior Research Foundation (NARSAD Young Investigator Award)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award (F32MH084460))National Institutes of Health (U.S.) (NIH grant (R03MH085224))Fundação para a Ciência e a Tecnologia (SFRH/BD/15231/2004)Fundação para a Ciência e a Tecnologia (SFRH/BD/15855/2005)Instituto Gulbenkian de Ciência (“Programa Gulbenkian de Doutoramento em Biomedicina” (PGDB, Oeiras, Portugal))University of Coimbra. Center for Neuroscience and Cell Biology (“Programa Doutoral em Biologia Experimental e Biomedicina” (CNC, Coimbra, Portugal)

Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer

Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50–60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2−/− mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC

THE STRUCTURAL DEPENDANCE OF HF VIBRATIONAL RED SHIFTS IN ArnHFAr_{n}HF CLUSTERS VIA HIGH RESOLUTION INFRARED SPECTROSCOPY

Author Institution: Joint Institute for Laboratory Astrophysics, University of Colorado, and National Institute of Standards and Technology, and the Department of Chemistry and Biochemistry, University of ColoradoThe rotationally resolved HF stretching spectra of $Ar_{n}F. n-1-4$, have been observed using a slit jet, difference frequency infrared laser spectrometer. The red shift of the HF vibrational frequency is shown to be sensitively dependent on the placement of the Ar with respect to the HF dipole moment: the largest incremental red shift is observed for the linear ArHF. The n-1-3 red shifts rapidly approach the values observed in an Ar matrix suggesting that only the nearest neighbors contribute significantly to the perturbation of the HF vibrational frequency. The observed $Ar_{4}HF$ isomer places the fourth Ar in what would be the second layer from the HF and has little effect on the observed red shift. This supports the importance of the nearest neighbors in determining the HF vibrational frequency. In all spectra, no evidence for vibrational predissociation is observed, indicating an extremely long lived HF vibration within the cluste

HIGH RESOLUTION INFRARED SPECTRUM OF (HCl)2 - HCI STRETCH FUNDAMENTAL AND COMBINATION BAND ANALYSIS

Author Institution: Joint Institute for Laboratory Astrophysics, University of Colorado, and National Institute of Standards and Technology, and the Department of Chemistry and Biochemistry, University of ColoradoThe infrared spectrum of jet cooled $(HCl)_{3}$ has been obtained with a high resolution difference frequency infrared spectrometer. Transitions originating from each of the tunneling sublevels with excitation of both the $\nu_{1}$ (free HCl) and $\nu_{2}$ (bound HCl) for all three isotopic species have been observed. In addition, combination band transitions involving high frequency HCl stretch plus low frequency van der Waals vibrations have been observed. These transitions probe higher levels of the geared tunneling coordinate and help elucidate the details of the intermolecular potential energy surface for $HCl(v-1) + HCl(v-O)$ collisions

Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice

Abstract There is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 mg=kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24-28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies ( p < 0.01). CBF was increased ( p < 0.05), and inflammatory markers (TNF-a and IL-6; p < 0.05), activated microglial (F4=80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury

Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice

There is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 μg/kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24–28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies (p < 0.01). CBF was increased (p < 0.05), and inflammatory markers (TNF-α and IL-6; p < 0.05), activated microglial (F4/80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury

Cocaine use is associated with cerebral white matter hyperintensities in HIV disease

Abstract Background White matter hyperintensities (WMH), a marker of cerebral small vessel disease and predictor of cognitive decline, are observed at higher rates in persons with HIV (PWH). The use of cocaine, a potent central nervous system stimulant, is disproportionately common in PWH and may contribute to WMH. Methods The sample included of 110 PWH on antiretroviral therapy. Fluid‐attenuated inversion recovery (FLAIR) and T1‐weighted anatomical MRI scans were collected, along with neuropsychological testing. FLAIR images were processed using the Lesion Segmentation Toolbox. A hierarchical regression model was run to investigate predictors of WMH burden [block 1: demographics; block 2: cerebrovascular disease (CVD) risk; block 3: lesion burden]. Results The sample was 20% female and 79% African American with a mean age of 45.37. All participants had persistent HIV viral suppression, and the median CD4+ T‐cell count was 750. Nearly a third (29%) currently used cocaine regularly, with an average of 23.75 (SD = 20.95) days in the past 90. In the hierarchical linear regression model, cocaine use was a significant predictor of WMH burden (β = .28). WMH burden was significantly correlated with poorer cognitive function (r = −0.27). Finally, higher WMH burden was significantly associated with increased serum concentrations of interferon‐γ‐inducible protein 10 (IP‐10) but lower concentrations of myeloperoxidase (MPO); however, these markers did not differ by COC status. Conclusions WMH burden is associated with poorer cognitive performance in PWH. Cocaine use and CVD risk independently contribute to WMH, and addressing these conditions as part of HIV care may mitigate brain injury underlying neurocognitive impairment