Exploring effects of chronic d ‐cycloserine administration on expression of GluN2 subunits and tripartite synaptic transmission in thalamocortical pathway

Abstract Background and Purpose d ‐cycloserine, N ‐methyl‐ d ‐aspartate/glutamate (NMDA) receptor co‐agonist (GluN2A/GluN2B partial and GluN2C super‐agonist), improves negative symptom of schizophrenia with narrow therapeutic window, but the mechanisms remains unclear. Experimental Approach Effects of chronic d ‐cycloserine administration (2–5 mg·kg −1 ) on sucrose preference of adult male rats were determined. Dose/concentration‐dependent effects of acute/chronic administrations of d ‐cycloserine (25–300 μM and 2–25 mg·kg −1 ) on expression of GluN2 subunits and associated transmission of l ‐glutamate/ d ‐serine/GABA were determined using microdialysis in adult male rats, primary cultured astrocytes (male/female neonatal rats) and capillary immunoblotting. Key Results d ‐cycloserine dose‐dependently increased release of astroglial l ‐glutamate/ d ‐serine and neuronal GABA in the thalamus and medial prefrontal cortex (mPFC) ( d ‐serine > GABA > l ‐glutamate), according to intrinsic activities (GluN2C > GluN2A [but unaffected GluN2B]). Chronic d ‐cycloserine dose‐dependently down‐regulated GluN2C > GluN2B > GluN2A (according to affinity) and attenuated d ‐cycloserine‐induced astroglial release of l ‐glutamate/ d ‐serine, dose dependently (GluN2C > GluN2A). Chronic exposure (25 μM) d ‐cycloserine down‐regulated GluN2C but increased GluN2C‐related astroglial l ‐glutamate/ d ‐serine release. Chronic exposure to >60μM d ‐cycloserine diminished GluN2C‐related astroglial release but activated GluN2A‐related release. Chronic administration of 2 but not 5‐mg·kg −1 d ‐cycloserine restored MK‐801‐induced decrease sucrose preference. Conclusion and Implications Chronic d ‐cycloserine (25 μM and 2 mg·kg −1 ) down‐regulated GluN2C without affecting GluN2A/GluN2B but increased GluN2‐related astroglial l ‐glutamate/ d ‐serine release. Higher d ‐cycloserine dose (>60 μM; >5 mg·kg −1 ) inactivated GluN2C, but increased GluN2A related astroglial release. These results indicate that dose‐dependent activation and inactivation of GluN2C by d ‐cycloserine is possibly involved in its efficacy on negative symptom of schizophrenia, but with a narrow therapeutic window.