Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

© 2020, The Author(s). Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates “dual-hit” neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics

The First Habitable-zone Earth-sized Planet from TESS. I. Validation of the TOI-700 System

We present the discovery and validation of a three-planet system orbiting the nearby (31.1 pc) M2 dwarf star TOI-700 (TIC 150428135). TOI-700 lies in the TESS continuous viewing zone in the Southern Ecliptic Hemisphere; observations spanning 11 sectors reveal three planets with radii ranging from 1 R⊕ to 2.6 R⊕ and orbital periods ranging from 9.98 to 37.43 days. Ground-based follow-up combined with diagnostic vetting and validation tests enables us to rule out common astrophysical false-positive scenarios and validate the system of planets. The outermost planet, TOI-700 d, has a radius of 1.19 ± 0.11 R⊕ and resides within a conservative estimate of the host star's habitable zone, where it receives a flux from its star that is approximately 86% of Earth's insolation. In contrast to some other low-mass stars that host Earth-sized planets in their habitable zones, TOI-700 exhibits low levels of stellar activity, presenting a valuable opportunity to study potentially rocky planets over a wide range of conditions affecting atmospheric escape. While atmospheric characterization of TOI-700 d with the James Webb Space Telescope (JWST) will be challenging, the larger sub-Neptune, TOI-700 c (R = 2.63 R⊕), will be an excellent target for JWST and future space-based observatories. TESS is scheduled to once again observe the Southern Hemisphere, and it will monitor TOI-700 for an additional 11 sectors in its extended mission. These observations should allow further constraints on the known planet parameters and searches for additional planets and transit timing variations in the system