Spatial working memory improved in
Spatial working memory improved in the Balb/c strain at a dose of VU0410120 (i.e., 30mg/kg) that disrupted spatial working memory in the Swiss Webster comparator strain. Consistent with a recent PET study in rhesus macaques suggesting a relationship between the extent of the dose-dependent occupancy of the GlyT1 site by a GlyT1 competitive inhibitor (i.e., Org 25935) and positive therapeutic effects on ketamine-induced deficits of spatial working memory (Castner et al., 2014), these mouse strain differences in sensitivity of spatial working memory performance to VU0410120 may reflect strain differences in the occupancy of the GlyT1 site by VU0410120. The study suggested that effective ranges of doses and GlyT1 occupancies of this inhibitor to improve ketamine-induced deficits of spatial working memory differed from doses and GlyT1 occupancies required to improve ketamine-induced hallucinatory-like behaviors (Castner et al., 2014). Also, impaired spatial working memory was observed when the GlyT1 inhibitor was administered in the control condition at a dose associated with a ~70% GlyT1 occupancy. Thus, the relation between Dehydroepiandrosterone occupancy and sensitivity to therapeutic effects of GlyT1 inhibition is influenced by the severity of NRH (i.e., less severe NRH may be associated with disruptive, as opposed to pro-cognitive, effects); further, antipsychotic effects may require higher occupancy levels of GlyT1 sites than are required for cognitive improvement. Moreover, doses of GlyT1 inhibitors above the ranges associated with pro-cognitive and antipsychotic effects may be detrimental and include sedative effects because they may promote internalization of NMDARs and/or lead to stimulation of strychnine-sensitive inhibitory glycine receptors enriched in brainstem. Conceivably, the availability of selective, high-affinity PET ligands for the GlyT1 site could serve as a biomarker of target engagement and guide decisions regarding dose titration and adjustment for specific target behaviors and symptom domains.
In addition to their lower liability for excitotoxicity than direct glycine or NMDAR agonists, GlyT1 inhibitors may offer greater spatial and temporal selectivity, especially after chronic oral administration; importantly, VU0410120 was shown to be orally available in the dog (Wolkenberg et al., 2009). Thus, rather than tonic stimulation of a wide distribution of NMDARs throughout the brain, selective GlyT1 inhibition may result in potentiation of synaptically-released glycine in specific brain regions in response to relevant social stimuli and cognitive challenges. Additionally, because GlyT1 inhibition may also increase synaptic availability of glycine at the inhibitory glycine receptor it may have a lesser liability to elicit seizures than other targeted NMDAR strategies (Socała et al., 2010). The current data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation, supporting exploration of GlyT1 inhibition as a therapeutic strategy for activation of the NMDAR in order to address the symptom domains of impaired sociability and cognition in persons with ASDs. However, as discussed, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggests that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy. In any event, GlyT1 inhibition is a promising pharmacotherapeutic strategy to explore in the treatment of patients with ASDs.
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Acknowledgment This research was supported by grant funding from Virginia's Commonwealth Health Research Board (#274-11-13). The authors also acknowledge the support they received from the Office of the Dean of Eastern Virginia Medical School.