RESUMEN
Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by abnormal social interactions, impaired language, and stereotypic and repetitive behaviours. Among genetically susceptible subpopulations, gut and dietary influences may play a role in etiology. Propionic acid (PPA), produced by enteric gut bacteria, crosses both the gut-blood and the blood-brain barrier. Previous research has demonstrated that repeated intracerebroventricular (ICV) infusions of PPA in adult rats produce behavioural and neuropathological changes similar to those seen in ASD patients, including hyperactivity, stereotypy, and repetitive movements. The current study examined dose and time related changes of exploratory and repetitive behaviours with the use of the hole-board task. Adult male Long-Evans rats received ICV infusions twice a day, 4â¯h apart, of either buffered PPA (low dose 0.052â¯M or high dose 0.26â¯M, pHâ¯7.5, 4⯵L/infusion) or phosphate buffered saline (PBS, 0.1â¯M) for 7 consecutive days. Locomotor activity and hole-poke behaviour were recorded daily in an automated open field apparatus (Versamax), equipped with 16 open wells, for 30â¯min immediately after the second infusion. In a dose dependent manner PPA infused rats displayed significantly more locomotor activity, stereotypic behaviour and nose-pokes than PBS infused rats. Low-dose PPA animals showed locomotor activity levels similar to those of PBS animals at the start of the infusion schedule, but gradually increased to levels comparable to those of high-dose PPA animals by the end of the infusion schedule, demonstrating a dose and time dependent effect of the PPA treatments.
Asunto(s)
Trastorno del Espectro Autista/psicología , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Locomoción/efectos de los fármacos , Propionatos/farmacología , Conducta Estereotipada/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Infusiones Intraventriculares , Masculino , Propionatos/administración & dosificación , Ratas , Factores de TiempoRESUMEN
Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD). Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.
Asunto(s)
Encéfalo/metabolismo , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Modelos Animales de Enfermedad , Enterobacteriaceae , Fosfolípidos/sangre , Propionatos/toxicidad , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Trastornos Generalizados del Desarrollo Infantil/inducido químicamente , Trastornos Generalizados del Desarrollo Infantil/patología , Preescolar , Enterobacteriaceae/metabolismo , Humanos , Infusiones Intraventriculares , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Propionatos/administración & dosificación , Ratas , Ratas Long-EvansRESUMEN
Recent studies have demonstrated intraventricular infusions of propionic acid (PPA) a dietary and enteric short-chain fatty acid can produce brain and behavioral changes similar to those observed in autism spectrum disorder (ASD). The effects of PPA were further evaluated to determine if there are any alterations in brain lipids associated with the ASD-like behavioral changes observed following intermittent intraventricular infusions of PPA, the related enteric metabolite butyric acid (BUT) or phosphate-buffered saline vehicle. Both PPA and BUT produced significant increases (p < 0.001) in locomotor activity (total distance travelled and stereotypy). PPA and to a lesser extent BUT infusions decreased the levels of total monounsaturates, total omega6 fatty acids, total phosphatidylethanolamine plasmalogens, the ratio of omega6 : omega3 and elevated the levels of total saturates in separated phospholipid species. In addition, total acylcarnitines, total longchain (C12-C24) acylcarnitines, total short-chain (C2 to C9) acylcarnitines, and the ratio of bound to free carnitine were increased following infusions with PPA and BUT. These results provide evidence of a relationship between changes in brain lipid profiles and the occurrence of ASD-like behaviors using the autism rodent model. We propose that altered brain fatty acid metabolism may contribute to ASD.