d-serine availability modulates prefrontal cortex inhibitory interneuron development and circuit maturation

• Published in: Scientific reports Vol. 13; no. 1; pp. 9595 - 11
• Main Authors: Folorunso, Oluwarotimi O., Brown, Stephanie E., Baruah, Jugajyoti, Harvey, Theresa L., Jami, Shekib A., Radzishevsky, Inna, Wolosker, Herman, McNally, James M., Gray, John A., Vasudevan, Anju, Balu, Darrick T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/340; 692/699/476/1373; 692/699/476/1799; Agonists; Animals; Craniocerebral Trauma; D-Serine; Enzymes; Female; Forebrain; Glutamate decarboxylase; Glutamic Acid; Glutamic acid receptors; Humanities and Social Sciences; Inhibitory postsynaptic potentials; Interneurons; L-Serine; Maturation; Mice; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neocortex; Neurosciences; Parvalbumin; Prefrontal Cortex; Pregnancy; Pyramidal cells; Science; Science (multidisciplinary); Serine racemase; Somatostatin; Telencephalon; Transcription factors; γ-Aminobutyric acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-35615-5

The proper development and function of telencephalic GABAergic interneurons is critical for maintaining the excitation and inhibition (E/I) balance in cortical circuits. Glutamate contributes to cortical interneuron (CIN) development via N -methyl- d -aspartate receptors (NMDARs). NMDAR activation requires the binding of a co-agonist, either glycine or d -serine. d -serine (co-agonist at many mature forebrain synapses) is racemized by the neuronal enzyme serine racemase (SR) from l -serine. We utilized constitutive SR knockout (SR −/− ) mice to investigate the effect of d -serine availability on the development of CINs and inhibitory synapses in the prelimbic cortex (PrL). We found that most immature Lhx6 + CINs expressed SR and the obligatory NMDAR subunit NR1. At embryonic day 15, SR −/− mice had an accumulation of GABA and increased mitotic proliferation in the ganglionic eminence and fewer Gad1  + (glutamic acid decarboxylase 67 kDa; GAD67) cells in the E18 neocortex. Lhx6 + cells develop into parvalbumin (PV+) and somatostatin (Sst+) CINs. In the PrL of postnatal day (PND) 16 SR −/− mice, there was a significant decrease in GAD67+ and PV+, but not SST + CIN density, which was associated with reduced inhibitory postsynaptic potentials in layer 2/3 pyramidal neurons. These results demonstrate that D-serine availability is essential for prenatal CIN development and postnatal cortical circuit maturation.