A progressive reduction in basal phosphorylation of glutamate receptors along postweaning development accompanies maturation of hippocampal theta-burst-induced LTP

Abstract Tackling developmental changes in long-term potentiation (LTP) expression during adolescence is crucial to understand disease susceptibility in neurodevelopmental disorders, epileptogenesis or drug abuse. This paper investigated the alterations in the ‘resting’ phosphorylation state of synaptic proteins essential for synaptic transmission and hippocampal LTP expression from weaning (3 weeks) to adulthood (12 weeks). Synaptic AMPA GluA1 and GluA2 subunit levels increased, yet to different extents, as the GluA1/GluA2 ratio also increased. Conversely, GluA1 phosphorylation in both Ser831 and Ser845 progressively decreased from weaning to adulthood, suggesting an enhanced availability of these sites for activity-dependent phosphorylation. In accordance, LTP induced by different theta-burst stimulation (TBS) intensities in the CA1 area of rat hippocampal slices enhanced gradually in this developmental period. In contrast, basal phosphorylation of GluN1, GluN2B and CaMKII increased during adolescence. Altogether, these findings suggest that alterations in AMPA receptor subunit composition and basal phosphorylation are crucial for the maturation of hippocampal LTP during adolescence, while a mild enhancement in synaptic CaMKII levels may further provide the necessary structural support to LTP expression and stability. Given the reported involvement of GluA1 phosphorylation changes in epileptogenesis and neurodevelopmental disorders, these findings provide important insights into hippocampal synaptic plasticity in normal and altered brain development and epileptogenesis.