Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May:145:104990.
doi: 10.1016/j.neuint.2021.104990. Epub 2021 Feb 13.

Forebrain expression of serine racemase during postnatal development

Oluwarotimi O Folorunso  1 , Theresa L Harvey  2 , Stephanie E Brown  2 , Cristina Cruz  3 , Ellie Shahbo  3 , Ismail Ajjawi  3 , Darrick T Balu  4
Affiliations

Forebrain expression of serine racemase during postnatal development

Oluwarotimi O Folorunso et al. Neurochem Int. 2021 May.

Abstract

N-methyl-D-aspartate receptors (NMDARs) are important for synaptogenesis, synaptic maturation and refinement during the early postnatal weeks after birth. Defective synapse formation or refinement underlie cognitive and emotional abnormalities in various neurodevelopmental disorders (NDDs), including schizophrenia (Sz) and autism spectrum disorder (ASD). Serine racemase (SR) is a neuronal enzyme that produces D-serine, a co-agonist required for full NMDAR activation. NMDAR hypofunction as a result of genetic SR elimination and reduced synaptic availability of D-serine reduces neuronal dendritic arborization and spine density. In adult mouse brain, the expression of SR parallels that of NMDARs across forebrain regions including the striatum, amygdala, hippocampus, and medial prefrontal cortex (mPFC). However, there have yet to be studies providing a detailed characterization of the spatial and temporal expression of SR during early periods of synaptogenesis. Here, we examined the postnatal expression of SR in cortical and subcortical brain regions important for learning, memory and emotional regulation, during the first four weeks after birth. Using dual-antigen immunofluorescence, we demonstrate that the number of SR+ neurons steadily increases with postnatal age across the mPFC, amygdala, hippocampus and striatum. We also identified differences in the rate of SR protein induction both across and within brain regions. Analyzing existing human post-mortem brain in situ data, there was a similar developmental mRNA expression profile of SRR and GRIN1 (GluN1 subunit) from infancy through the first decade of life. Our findings further support a developmental role for D-serine mediated NMDAR activation regulating synaptogenesis and neural circuit refinement, which has important implications for the pathophysiology of Sz and other NDDs.

Keywords: D-serine; GRIN1; N-methyl-D-aspartate receptor (NMDAR); Schizophrenia; Serine racemase; Synaptogenesis.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

DTB served as a consultant for LifeSci Capital and received research support from Takeda Pharmaceuticals. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
Quantification of serine racemase expressing neurons in prefrontal cortex regions across postnatal development.
Figure 2
Figure 2
Serine racemase expressing neurons in hippocampus across postnatal development.
Figure 3
Figure 3
Quantification of serine racemase expressing neurons in amygdala regions across postnatal development.
Figure 4
Figure 4
Quantification of serine racemase expressing neurons in striatal regions across postnatal development
Figure 5
Figure 5
Expression profile of SRR and GRIN1 in the human developing brain.
See this image and copyright information in PMC

References

    1. Alvarez RJ, Pafundo DE, Zold CL, Belforte JE, 2020. Interneuron NMDA Receptor Ablation Induces Hippocampus-Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia. J Neurosci 40, 3304–3317. - PMC - PubMed
    1. Balan L, Foltyn VN, Zehl M, Dumin E, Dikopoltsev E, Knoh D, Ohno Y, Kihara A, Jensen ON, Radzishevsky IS, Wolosker H, 2009. Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane. Proc Natl Acad Sci U S A. - PMC - PubMed
    1. Balleine BW, Liljeholm M, Ostlund SB, 2009. The integrative function of the basal ganglia in instrumental conditioning. Behav Brain Res 199, 43–52. - PubMed
    1. Balu DT, 2016. The NMDA Receptor and Schizophrenia: From Pathophysiology to Treatment. Adv Pharmacol 76, 351–382. - PMC - PubMed
    1. Balu DT, Basu AC, Corradi JP, Cacace AM, Coyle JT, 2012. The NMDA receptor co-agonists, d-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. Neurobiol Dis 45, 671–682. - PMC - PubMed

Publication types

MeSH terms

Substances