4 research outputs found
Spatial Learning Depends on Both the Addition and Removal of New Hippocampal Neurons
The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons
A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes
ABSTRACT Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored so far. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) task. Notably, this phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate itself might promote the accumulation of this amino acid. Consistent with this idea, lactate increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors in a PP-dependent manner. By establishing a mechanistic link between lactate, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes
Structural, Kinetic, and Pharmacodynamic Mechanisms of d‑Amino Acid Oxidase Inhibition by Small Molecules
We characterized the mechanism and
pharmacodynamics of five structurally
distinct inhibitors of d-amino acid oxidase. All inhibitors
bound the oxidized form of human enzyme with affinity slightly higher
than that of benzoate (<i>K</i><sub>d</sub> ≈ 2–4
μM). Stopped-flow experiments showed that pyrrole-based inhibitors
possessed high affinity (<i>K</i><sub>d</sub> ≈ 100–200
nM) and slow release kinetics (<i>k</i> < 0.01 s<sup>–1</sup>) in the presence of substrate, while inhibitors with
pendent aromatic groups altered conformations of the active site lid,
as evidenced by X-ray crystallography, and showed slower kinetics
of association. Rigid bioisosteres of benzoic acid induced a closed-lid
conformation, had slower release in the presence of substrate, and
were more potent than benzoate. Steady-state d-serine concentrations
were described in a PK/PD model, and competition for d-serine
sites on NMDA receptors was demonstrated in vivo. DAAO inhibition
increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where
DAAO can exert a neuromodulatory role