Serine Racemase Expression by Striatal Neurons

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• D-serine, synthesized by serine racemase (SR), acts as a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDARs).
• SR and D-serine are primarily found in neurons, with limited expression in quiescent astrocytes.
• The role of SR and D-serine in specific neuronal populations, particularly in the striatum, requires further investigation.

Purpose of the Study:

• To investigate the localization of D-serine and SR within the mouse striatum.
• To determine the functional impact of genetically silencing SR expression specifically in GABAergic interneurons on behavior.
• To elucidate the role of D-serine synthesized by striatal GABAergic neurons in mediating dopaminergic stimulant effects.

Main Methods:

• Examined SR and D-serine localization in the mouse striatum using immunohistochemistry and genetic manipulation.
• Generated and analyzed GABAergic interneuron-specific SR knockout mice (iSR-/-).
• Assessed behavioral responses to cocaine, including stimulant and anxiety-related effects, in iSR-/- mice.

Main Results:

• SR expression was significantly reduced in iSR-/- mice, primarily in the striatum, with only a marginal decrease in D-serine levels.
• SR-positive cells in the striatum strongly co-localized with DARPP32, D1, and D2 dopamine receptors, indicating expression in medium spiny neurons.
• iSR-/- mice exhibited a blunted response to the stimulant and hedonic effects of cocaine, without alterations in anxiety-related behaviors.

Conclusions:

• GABAergic medium spiny neurons in the striatum robustly express SR and likely synthesize D-serine.
• Striatal D-serine, produced by SR in GABAergic neurons, plays a crucial role in mediating the stimulant effects of drugs like cocaine.
• SR-mediated D-serine synthesis in GABAergic neurons may function in an autocrine manner to modulate NMDAR excitability.