Abstract
d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.
Highlights
This compensatory response could explain why NMDAR activation and long-term potentiation (LTP) expression in extracellular recordings are not affected in serine racemase (SR)-KO mice and why memory abilities are preserved
Functional deficits are recorded in hippocampal slices from the SR-KO mice when the intrinsic GABA activity is pharmacologically blocked with bicuculline, indicating that a change in the E/I balance could contribute to maintaining functional plasticity of the CA1 hippocampal networks in the absence of d-serine
We observed that LTP expression and NMDAR activation in SR-KO mice were not affected in control conditions, but were reduced when the GABAA receptor activity was pharmacologically suppressed
Summary
The role of d-serine was investigated in brain slices from knockout mice with genetic deletion of the synthesizing enzyme serine racemase (SR) that converts L- into d-serine [18,19,20,21]. There is an apparent discrepancy regarding changes in synaptic plasticity and NMDAR activation at CA3/CA1 hippocampal synapses. Studies of isolated excitatory glutamate transmission on CA1 pyramidal cells reported LTP deficits and altered NMDAR activation in slices from SR-KO mice [23,26,27]. In order to investigate this possibility, we reinvestigated LTP expression and NMDAR synaptic activity with extracellular recordings in CA1 hippocampal networks of SR-KO mice before and after the alteration of the GABAergic inhibitory tone by the GABAR antagonist bicuculline. We found that SR deletion attenuates the inhibitory tone, which helps to preserve overall network activity and behavior
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