D-serine improves dimensions of the sociability deficit of the genetically-inbred Balb/c mouse strain
ABSTRACT The Balb/c mouse strain shows quantitative deficits of sociability and is behaviorally-hypersensitive to MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist. D-Serine (560mg/kg, intraperitoneally), a full agonist for the obligatory glycine co-agonist binding site on the NMDA receptor, increased the amount of time Balb/c mice spend in a compartment containing the enclosed social stimulus mouse and the amount of time Balb/c mice spend exploring (sniffing) an inverted cup containing the enclosed social stimulus mouse in a standard sociability apparatus. These effects of D-serine on the impaired sociability of the Balb/c mouse strain were not due to a "nonspecific" effect on locomotor activity; importantly, the locomotor activity of the Balb/c mouse strain decreases in the presence of an enclosed or freely-moving social stimulus mouse. The data suggest that dimensions of the impaired sociability of the Balb/c mouse strain may be improved by targeted NMDA receptor agonist interventions.
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ABSTRACT: Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in-silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.Neurochemistry International 01/2014; DOI:10.1016/j.neuint.2014.01.002 · 2.65 Impact Factor
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ABSTRACT: Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with complex symptoms and unclear, multi-factorial pathogenesis. Animal (rodent) models of ASD-like behavior are extensively used to study genetics, circuitry and molecular mechanisms of ASD. The evolutionarily conserved nature of social behavior and its molecular pathways suggests that alternative experimental models can be developed to complement and enhance the existing rodent ASD paradigms. The zebrafish (Danio rerio) is rapidly becoming a popular model organism in neuroscience and biological psychiatry to study brain function, model human brain disorders and explore their genetic or pharmacological modulation. Representing highly social animals, zebrafish emerge as a strong potential model organism to study normal and pathological social phenotypes, as well as several other ASD-like symptoms. Here, we discuss the developing utility of zebrafish in modeling ASD as a new emerging field in translational neuroscience and drug discovery.Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2013; DOI:10.1016/j.pnpbp.2013.11.014 · 4.03 Impact Factor
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ABSTRACT: Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+) Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior, which may be due to an upregulation of Raf/ERK, upstream intermediates in mTOR signaling. In prior work, D-cycloserine, a partial glycineB site agonist that targets the N-methyl-D-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p. x four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model.Brain research bulletin 11/2013; DOI:10.1016/j.brainresbull.2013.11.005 · 2.97 Impact Factor