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  • Consistent with these observations impaired transduction of

    2022-01-14

    Consistent with these observations, impaired transduction of the glutamate signal by NMDARs (i.e., NMDA receptor hypofunction [NRH]) by parvalbumin-containing GABAergic inhibitory interneurons is implicated in mediating social deficits, a domain of psychopathology responsible for poor functional outcomes in schizophrenia and ASDs (Billingslea et al., 2014). Relative to mice expressing the NR1 subunit, mice with conditionally knocked out integrin inhibitors of the NR1 subunit on parvalbumin-containing interneurons were significantly impaired in sociability, induction and maintenance of hippocampal long-term potentiation, and nest-building behavior; these data suggest that this conditional NR1-knockout mouse models aspects of the social deficit seen in schizophrenia and ASDs, and supports a role for functional NMDARs on parvalbumin-containing interneurons in the activity-dependent plasticity of downstream pyramidal neurons (Billingslea et al., 2014). NRH would result in reduced central inhibition or increased central excitation, which has implications for pharmacotherapy targeting this core social deficit domain of psychopathology. VU0410120 (2,4-dichloro-N-((4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl)methyl)benzamide) is a non-sarcosine derived derivative of a 4,4-disubstituted piperidine GlyT1 inhibitor, which has high selectivity for the GlyT1 site; the IC50 for the GlyT1 site is 26nM, whereas its IC50 for the GlyT2 “taurine transporter” is greater than 30μM (Wolkenberg et al., 2009). Because persons with ASD display impaired sociability, cognitive deficits and stereotypic behaviors and the NMDAR is involved in regulating sociability, the current study explored effects of VU0410120 on sociability, spatial working memory, and stereotypic behaviors elicited in a social setting in Balb/c and Swiss Webster mice.
    Materials and methods
    Results
    Discussion The current study evaluated dose-dependent effects of VU0410120 on measures of sociability, stereotypic behaviors and cognition in Balb/c and Swiss Webster mice. Data collected in Session II confirmed earlier work reporting that Balb/c mice show no preference for the compartment containing the enclosed stimulus mouse versus the compartment containing the empty inverted cup, nor do they spend more time sniffing/exploring the enclosed stimulus mouse than the empty inverted cup (Brodkin, 2007, Burket et al., 2010b, Deutsch et al., 2011, Deutsch et al., 2012, Fairless et al., 2013, Jacome et al., 2011b, Jacome et al., 2011c, Sankoorikal et al., 2006). These data support the Balb/c strain as a mouse model of ASDs. Moreover, as shown in Session II, pretreatment of Balb/c mice with VU0410120 increased the salience and exploration of the stimulus mouse in a dose-dependent manner; increased social exploration is reflected in the reduced initial latency to approach the enclosed stimulus mouse. Importantly, VU0410120 did not increase the locomotor activity of Balb/c mice in Sessions II and III; thus, its prosocial effects in this strain are not likely to be epiphenomena of a primary effect on locomotor activity (Supplementary Fig. S2). Prosocial effects of VU0410120 in the Balb/c mouse strain are also supported by its ability to increase discrete episodes of social approach and cause complementary decreases in discrete episodes of social avoidance. Further, the significantly increased total time Balb/c mice spend pursuing the stimulus mouse in session III is also consistent with a positive effect of VU0410120 on social exploration. Very interestingly, VU0410120 diminished rearing behavior in the Swiss Webster strain and self-grooming behavior in both test strains, while increasing jumping and burrowing behaviors primarily in the Swiss Webster strain. These data suggest that circuitry underlying these stereotypic behaviors differ and genetic factors influence their sensitivity to glycinergic interventions (i.e., rearing and self-grooming are reduced by VU0410120, whereas VU0410120 causes emergence or worsening of jumping and burrowing in the Swiss Webster strain at doses associated with prosocial effects in the Balb/c strain). Thus, in order to optimize potential therapeutic effects on impaired sociability and cognition while avoiding emergence and worsening of stereotypic behaviors, individualized dosage titration strategies may be an important consideration when translational clinical trials of GlyT1 inhibitors are implemented in patients with ASDs. Further, stratification of patients according to relevant polymorphisms of NMDA receptor signaling pathways may help to identify patient subgroups more likely to show positive therapeutic effects as well as adverse effects, particularly heightened sensitivity to specific stereotypic behaviors (Endele et al., 2010, Mori et al., 2011). In our paradigms, we study stereotypic behaviors in the context of social “challenges,” which is important because stereotypic behaviors emerging or worsening in social settings and during social interactions exacerbate difficulties patients with ASDs have with socialization (Campbell et al., 1990, Goldman et al., 2009). From this latter perspective, in the Balb/c mouse model of ASDs, VU0410120 appears to have the desirable properties of therapeutically targeting impaired sociability and deficits of spatial working memory at doses that do not cause emergence or worsening of stereotypies during social encounters; in fact, at least in the Swiss Webster comparator strain, VU0410120 actually lessens the severity of rearing and self-grooming behaviors.