Cellular and molecular mechanisms involved in LTP induced by mild theta-burst stimulation in hippocampal slices from young male rats: from weaning to adulthood

Long-term potentiation (LTP) is a highly studied cellular process yet determining the transduction and GABAergic pathways that are the essential vs. modulatory for LTP elicited by theta-burst stimulation (TBS) in the hippocampal CA1 area is still elusive, due to the use of different TBS intensities, patterns, or different rodent/cellular models. We now characterized the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5×4) (5 bursts of 4 pulses delivered at 100Hz) lasted for up to 3h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15×4) or three TBS (15×4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP-enhancing drugs. LTP induced by TBS (5×4) in young adults was fully dependent on NMDA receptor and CaMKII activity but independent of PKA or PKC activity. Furthermore, it was partially dependent on GABA B receptor activation and was potentiated by GABA A receptor blockade and less by GAT-1 transporter blockade. AMPA GluA1 phosphorylation on Ser 831 (CaMKII target) but not GluA1 Ser 845 (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser 438 (CaMKII target) but not at Thr 602 or Thr 607 (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC or kinases of the ERK/MAPK family although important modulators of TBS (5×4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus. Graphical abstract LTP induced by theta-burst stimulation (TBS) in young adult male rat hippocampal CA1 area is increasingly more robust with the number of bursts and number of spaced TBS trains. LTP induced by TBS shows developmental maturation increasing potentiation from weaning to adulthood. Expression of LTP induced by mild TBS (5×4) in young adults requires NMDA receptor and CaMKII activity and AMPA Ser831 phosphorylation, but not PKA or PKC activity, and is likely curtailed by Kv4.2 Ser438 phosphorylation.