1. d-serine availability modulates prefrontal cortex inhibitory interneuron development and circuit maturation
- Author
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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, and Balu, Darrick T
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Pediatric ,Neurological ,Female ,Pregnancy ,Animals ,Mice ,Interneurons ,Prefrontal Cortex ,Craniocerebral Trauma ,Glutamic Acid ,Neocortex - Abstract
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.
- Published
- 2023