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  • It is possible that maternal separation induced


    It is possible that maternal separation-induced USV in neonatal rodents is not a good model of adult anxiety for examining GlyT1 inhibitors, if the expression levels of GlyT1, GlyA, and GlyB markedly differ between pups and adults. However, several reports provide evidence that this is not the case. Lall et al. (2012) have reported that the expression levels of both GlyT1 and GlyA differ by 20% in the K02288 stems of 10-day-old mouse pups and adult mice. Suen et al. (1998) have reported that the protein levels of NR1 subunits in the rat cortical postsynaptic density is 1.6-fold greater in adult rats than in rats at postnatal day 10. Although these differences are unlikely to change the conclusions of the present study, other paradigms such as the elevated plus maze test should be examined in adult rodents to provide further confirmatory evidence of our conclusions. In conclusion, the present data suggest that the anxiolytic effects of GlyT1 inhibitors are mediated through GlyA but not through GlyB. Several GlyT1 inhibitors are currently in clinical development for the treatment of schizophrenia and obsessive–compulsive disorder (Umbricht et al., 2014; Identifier: NCT01674361), and a recent clinical study has demonstrated that sarcosine, a GlyT1 inhibitor, improves psychic anxiety, as assessed by means of the 17-item Hamilton Depression Rating Scale, in patients with major depression (Huang et al., 2013). Our findings further demonstrate the anxiolytic effects of GlyT1 inhibitors and provide new insights into the mechanism of these anxiolytic effects.
    Introduction Glycine and d-serine are the endogenous obligatory co-agonists of the NMDA receptor (NMDAR), a glutamate-gated ion channel receptor; they increase the likelihood that l-glutamate will be effective in opening the channel to promote Ca conductance (Millan, 2005, Papouin et al., 2012). Therapeutically targeting the NMDAR is challenging because these receptors have widely-distributed synaptic and extrasynaptic locations, the latter are defined by their distance from the postsynaptic density (Hardingham and Bading, 2010, Parsons and Raymond, 2014, Vizi et al., 2013). Further, synaptic and extrasynaptic receptors differ in subunit composition, and in their preferences for d-serine (i.e., synaptic) or glycine (i.e., extrasynaptic) as obligatory co-agonists (Vizi et al., 2013). There are some data suggesting that stimulation of synaptic NMDAR can be “neuroprotective,” whereas (excessive) stimulation of extrasynaptic receptors may be associated with “neurotoxicity” (Hardingham and Bading, 2010, Vizi et al., 2013). Importantly, several studies have shown that enhancing NMDAR function improved ASD-like phenotypes in genetic mouse models of Autism Spectrum Disorders (ASDs) (Billingslea et al., 2014, Burket et al., 2013, Deutsch et al., 2012, Halene et al., 2009, Jacome et al., 2011a, Labrie et al., 2008, Saunders et al., 2013, Wellmann et al., 2014, Won et al., 2012). Because glycine works cooperatively with glutamate to promote opening of the NMDAR, one prominent therapeutic strategy involves inhibition of the glycine type 1 transporter (GlyT1). The GlyT1 is a member of the family of Na+/Cl−-dependent glycoprotein transporters with 12-transmembranous domains, which include the transporters for proline, monoamines and GABA, and is widely expressed on glia and neurons in forebrain (Castner et al., 2014). Theoretically, therapeutic targeting of NMDAR with a GlyT1 inhibitor would be less excito/neurotoxic than administration of direct glycine/glutamate agonists and would also act locally to promote synaptic concentrations of endogenous glycine (Billingslea et al., 2014, Castner et al., 2014). The Balb/c mouse strain displays behaviors relevant to ASDs, including impaired sociability (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). For example, relative to the C57Bl/6J and Swiss Webster comparator strains, Balb/c mice display decreased locomotor activity in the presence of a salient social stimulus mouse, spend less time exploring and in the vicinity of an enclosed social stimulus mouse, and make fewer discrete episodes of social approach when they interact freely with the stimulus mouse, among other reliably rated behaviors (Benson et al., 2013, 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). d-Cycloserine, a partial glycineB agonist, improves the sociability of the Balb/c mouse, consistent with data suggesting that NMDAR activation regulates sociability, and altered endogenous tone of NMDAR-mediated neurotransmission in Balb/c mice (Benson et al., 2013, Burket et al., 2010a, Deutsch et al., 1997, Deutsch et al., 1998, Deutsch et al., 2011, Deutsch et al., 2012, Jacome et al., 2011b). Specifically, relative to other outbred and inbred strains, Balb/c mice are hypersensitive to behavioral effects of MK-801 (dizocilpine), an uncompetitive NMDAR antagonist. Specifically, Balb/c mice are more sensitive to the ability of MK-801 to elicit irregular episodes of intense jumping behavior, termed “popping,” and circling behavior, and antagonize electrically-precipitated tonic hindlimb extension (Billingslea et al., 2003, Burket et al., 2010a, Deutsch et al., 1997, Deutsch et al., 1998). Importantly, the “highly sociable” C57Bl/6J strain of mouse prefers exploring d-cycloserine-pretreated Balb/c mice to vehicle-pretreated Balb/c mice, suggesting that d-cycloserine normalizes the social signals emitted by Balb/c mice (Benson et al., 2013).