D-serine improves dimensions of the sociability deficit of the genetically-inbred Balb/c mouse strain

Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA 23507-1912, United States.
Brain research bulletin (Impact Factor: 2.72). 11/2010; 84(1):12-6. DOI: 10.1016/j.brainresbull.2010.10.010
Source: PubMed


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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    • "Because the Balb/c mouse is behaviorally hypersensitive to MK-801, D-cycloserine and D-serine, a partial and full glycine B agonist acting at the NMDA receptor, respectively, were investigated for their ability to improve sociability in this mouse strain. The data showed that these targeted NMDA receptor agonist interventions improved several quantitative measures of sociability in 4-and 8-week-old Balb/c mice (Deutsch et al., 2011a, 2012; Jacome et al., 2011a). Further, the C57Bl/6 strain of mouse spent more time exploring D-cycloserinetreated Balb/c mice than they did exploring vehicle-treated Balb/c mice, suggesting that D-cycloserine " normalized " social signals emitted by the Balb/c strain (Benson et al., 2013). "
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    ABSTRACT: Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2015; 60. DOI:10.1016/j.pnpbp.2015.02.009 · 3.69 Impact Factor
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    • "The laboratory adopted an established mouse behavioral procedure for the quantitative assessment of sociability (Brodkin, 2007; Burket et al., 2013, 2010; Crawley, 2007, 2004; Deutsch et al., 2012, 2011; Jacome et al., 2011a; Sankoorikal et al., 2006). Briefly, in the first session, a test mouse is placed in the middle compartment and allowed to acclimate to the sociability apparatus for 5 min. "
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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; 100. DOI:10.1016/j.brainresbull.2013.11.005 · 2.72 Impact Factor
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    • "BALB/c mice also exhibit low sociability, exaggerated aggression, enlarged brain mass, low serotonin levels (Brodkin, 2007) and decreased passive social behavior (Fairless, Katz, 2013), suggesting them as a genetic model of ASD-related states. Systemic treatment of BALB/c mice with MK-801, an allosteric inhibitor of the glutamatergic (NMDA) receptors, elicits stereotypic circling behavior (Burket et al. , 2010), whereas D-serine, a NMDA receptor agonist, increases sociability (Jacome et al. , 2011). Together, this suggests the involvement of glutamatergic pathways in the pathogenesis of locomotor stereotypies and social impairment in the BALB/c mouse model of ASD-like behavior. "
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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.
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