Converging Evidence on D-Amino Acid Oxidase–Dependent Enhancement of Hippocampal Firing Activity and Passive Avoidance Learning in Rats

Abstract

Background N-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogenous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine and modulates a variety of physiological functions, including cognitive behavior. Methods Here, we examined the effects of a novel 4-hydroxypyridazin-3(2H)-one derivative DAAO inhibitor, Compound 30 (CPD30), on passive avoidance learning and on neuronal firing activity in rats. Results D-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively reversed MK-801–induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal neurons significantly increased firing rate and enhanced their responses to locally applied NMDA. CPD30 also enhanced hippocampal firing activity after systemic administration. In 0.1- to 1.0-mg/kg doses, CPD30 increased spontaneous and NMDA-evoked firing activity of the neurons. Effects of CPD30 on NMDA responsiveness emerged faster (at 10 minutes post-injection) when a 1.0-mg/kg dose was applied compared with the onset of the effects of 0.1 mg/kg CPD30 (at 30 minutes post-injection). Conclusions The present results confirm that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement. Our findings further facilitate the understanding of the cellular mechanisms underlying the behavioral effects of DAAO inhibition in the mammalian brain.

Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

“…DAAO selectively catalyzes the oxidative deamination of natural D-serine to produce imino acid, which is naturally hydrolyzed to the corresponding α-keto acids and ammonia (Pollegioni et al, 2018). Related research has confirmed that inhibition of DAAO can lead to increased D-serine in the brain, thereby regulating a variety of neurophysiological functions including cognitive behavior (Nagy et al, 2020). Meanwhile, it was also found that NMDAR antagonists (MK801 and cocaine) could increase the release of glutamate and decrease the expression of SR and DAAO.…”

An Overview of the Involvement of D-Serine in Cognitive Impairment in Normal Aging and Dementia

“…DAAO plays a key role in the process of oxidative stress and results in formation of ROS; through this effect and its regulatory function on NMDARs by reducing levels of D-serine, DAAO may play an important role in the process of aging and age-related cognitive decline (109). Nagy et al (110) studied the effects of the DAAO inhibitor CPD30 on passive avoidance learning and neuronal firing activity in rats and concluded that inhibition of DAAO is an effective strategy for cognitive enhancement; CPD30 increased hippocampal firing and reversed MK-801-induced memory impairment in the passive avoidance test.…”

DAAO mutant sites among different mice strains and their effects on enzyme activity

“…On the other hand, the mutation and knock-down of daao gene in the spinal cord and the application of DAAO inhibitors (Compound 8, CBIO, Compound SUN, AS057278, and sodium benzoate) have been shown to reduce formalin-induced tonic pain [8][9][10][11], neuropathic pain [1,12], bone cancer pain [2], and mechanical hyperalgesia caused by sleep deprivation [13]. A natural DAAO mutant mouse with a single point mutation (G181R) was discovered, and applied to study its function on memory performance for the complete lack of DAAO activity [14,15]. The related behavioral pharmacological results were also con rmed by using the DAAO inhibitor and DAAO knockout mice, which was related to enhanced hippocampal long-term potentiation observed in the mutant mice [16,17].…”