Adolescent maturation of dorsolateral prefrontal cortex glutamate:GABA and cognitive function is supported by dopamine-related neurobiology

Abstract

Developmental changes in prefrontal cortex (PFC) excitatory (glutamatergic, Glu) and inhibitory (gamma- aminobutryic acid, GABA) neurotransmitter balance (E:I) have been identified during human adolescence, potentially reflecting a critical period of plasticity that supports the maturation of PFC-dependent cognition. Animal models implicate increases in dopamine (DA) in regulating changes in PFC E:I during critical periods of development, however, mechanistic relationships between DA and E:I have not been studied in humans. Here, we used high field (7T) echo planar imaging (EPI) in combination with Magnetic Resonance Spectroscopic Imaging (MRSI) to assess the role of basal ganglia tissue iron—reflecting DA neurophysiology—in longitudinal trajectories of dorsolateral PFC Glu, GABA, and their relative levels (Glu:GABA) and working memory performance from adolescence to adulthood in 153 participants (ages 10–32 years old, 1–3 visits, 272 visits total). Using generalized additive mixed models (GAMMs) that capture linear and non-linear developmental processes, we show that basal ganglia tissue iron increases during adolescence, and Glu:GABA is biased towards heightened Glu relative to GABA early in adolescence, decreasing into adulthood. Critically, variation in basal ganglia tissue iron was linked to different age-related trajectories in Glu:GABA and working memory. Specifically, individuals with higher levels of tissue iron showed a greater degree of age-related declines in Glu and Glu:GABA, resulting in lower Glu relative to GABA (i.e., higher GABA relative to Glu) in young adulthood. Variation in tissue iron additionally moderated working memory trajectories, as higher levels of tissue iron were associated with steeper age-related improvements and better performance into adulthood. Our results provide novel evidence for a model of critical period plasticity whereby individual differences in DA may be involved in fine-tuning PFC E:I and PFC-dependent cognitive function at a critical transition from adolescence into adulthood.