D-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity.

The partial N-methyl-D-aspartate receptor (NMDAR) agonist D-Cycloserine (DCS) has been evaluated for the treatment of a wide variety of psychiatric disorders, including dementia, schizophrenia, depression and for the augmentation of exposure-based psychotherapy. Most if not all of the potential psychiatric applications of DCS target an enhancement or restitution of cognitive functions, learning and memory. Their molecular correlate is long-term synaptic plasticity; and many forms of synaptic plasticity depend on the activation of NMDA receptors. Here, we comprehensively examined the modulation of different forms of synaptic plasticity in the hippocampus by DCS and its mechanism. We found that DCS positively modulates NMDAR-dependent forms of long-term synaptic plasticity (long-term synaptic potentiation, LTP, and long-term synaptic depression, LTD) in hippocampal brain slices of juvenile rats without affecting basal synaptic transmission. DCS binds to the D-serine/glycine binding site of the NMDAR. Pharmacological inhibition of this site prevented the induction of LTP, whereas agonism at the D-serine/glycine binding site augmented LTP and could functionally substitute for weak LTP induction paradigms. The most probable origin of endogenous D-serine are astrocytes, and its exocytosis is regulated by astrocytic metabotropic glutamate receptors (mGluR1). Functional eradication of astrocytes, inhibition of mGluR1 receptors and G-protein signaling in astrocytes adjacent to postsynaptic neurons prevented the induction of NMDAR-dependent forms of LTP and LTD. Our results support the enhancement of a bidirectional range of NMDAR-dependent hippocampal synaptic plasticity by DCS and D-serine-mediated gliotransmission. Therefore, the D-serine/glycine-binding site in NMDAR is a major target for psychopharmacological interventions targeting plasticity-related disorders.

Cobalt Corroles as Electrocatalysts for Water Oxidation: Strong Effect of Substituents on Catalytic Activity.

Two Co(III) complexes (1Py2 and 2Py2) of new corrole ligands H3L1 (5,15-bis(p-methylcarboxyphenyl)-10-(o-methylcarboxyphenyl)corrole) and H3L2 (5,15-bis(p-nitrophenyl)-10-(o-methylcarboxyphenyl)corrole) with two apical pyridine ligands have been synthesized and thoroughly characterized by cyclic voltammetry, UV-vis-NIR, and EPR spectroscopy, spectroelectrochemistry, single-crystal X-ray diffraction studies, and DFT methods. Complexes 1Py2 and 2Py2 possess much lower oxidation potentials than cobalt(III)-tris-pentafluorophenylcorrole (Co(tpfc)) and similar corroles containing pentafluorophenyl (C6F5) substituents, thus allowing access to high oxidation states of the former metallocorroles using mild chemical oxidants. The spectroscopic (UV-vis-NIR and EPR) and electronic properties of several oxidation states of these complexes have been determined by a combination of the mentioned methods. Complexes 1Py2 and 2Py2 undergo three oxidations within 1.3 V vs FcH+/FcH in MeCN, and we show that both complexes catalyze water oxidation in an MeCN/H2O mixture upon the third oxidation, with kobs (TOF) values of 1.86 s-1 at 1.29 V (1Py2) and 1.67 s-1 at 1.37 V (2Py2). These values are five times higher than previously reported TOF values for C6F5-substituted cobalt(III) corroles, a finding we ascribe to the additional charge in the corrole macrocycle due to the increased oxidation state. This work opens up new possibilities in the study of metallocorrole water oxidation catalysts, particularly by allowing spectroscopic probing of high-oxidation states and showing strong substituent-effects on catalytic activity of the corrole complexes.