Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Abstract

An age-associated decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic function contributes to impaired synaptic plasticity and is associated with cognitive impairments. Levels of serine racemase (SR), an enzyme that synthesizes D-serine, an NMDAR co-agonist, decline with age. Thus, enhancing NMDAR function via increased SR expression in middle age, when subtle declines in cognition emerge, was predicted to enhance performance on a prefrontal cortex-mediated task sensitive to aging. Middle-aged (~12 mo) male Fischer-344 rats were injected bilaterally in the medial prefrontal cortex (mPFC) with viral vector (LV), SR (LV-SR) or control (LV-GFP). Rats were trained on the operant attentional set-shift task (AST) to examine cognitive flexibility and attentional function. LV-SR rats exhibited a faster rate of learning compared to controls during visual discrimination of the AST. Extradimensional set shifting and reversal were not impacted. Immunohistochemical analyses demonstrated that LV-SR significantly increased SR expression in the mPFC. Electrophysiological characterization of synaptic transmission in the mPFC slices obtained from LV-GFP and LV-SR animals indicated a significant increase in isolated NMDAR-mediated synaptic responses in LV-SR slices. Thus, results of the current study demonstrated that prefrontal SR upregulation in middle age rats can improve learning of task contingencies for visual discrimination and increase glutamatergic synaptic transmission, including NMDAR activity.

Serine racemase expression profile in the prefrontal cortex and hippocampal subregions during aging in male and female rats

“…Moreover, electrophysiological recordings revealed a significant enhancement in NMDA receptor-mediated synaptic responses recorded from the mPFC as a result of the upregulation of SR expression. These observations suggest a link between the increased expression of SR, improved attentional function, and enhanced NMDA receptor-mediated synaptic responses, shedding light on the potential neurobiological mechanisms underlying the observed behavioral effects [ 60 ]. The present findings provide experimental support for the hypothesis positing that the reduction in SR expression may be a contributing factor to the decline in NMDA receptor function and potentially exert a negative influence on cognitive function.…”

“…Additionally, our recent results demonstrate that the viral vector-mediated increase in SR expression within the mPFC of middle-aged rats led to effective contingency acquisition in visual discrimination tasks, likely attributable to improved attentional function. In addition, electrophysiological recordings revealed a substantial enhancement in NMDA receptor-mediated synaptic responses recorded from the mPFC following the upregulation of SR expression [ 60 ]. Therefore, we asked whether SR could be reduced in the prefrontal cortex of our rat model.…”