Hippocampal CA1 theta burst-induced LTP from weaning to adulthood: Cellular and molecular mechanisms in young male rats revisited

Abstract

Long-term potentiation (LTP) is a highly studied cellular process, yet determining the transduction and gamma aminobutyric acid (GABAergic) pathways that are the essential versus modulatory for LTP elicited by theta burst stimulation (TBS) in the hippocampal Cornu Ammonis 1 (CA1) area is still elusive, due to the use of different TBS intensities, patterns or different rodent/cellular models. We now characterised 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 (5x4) (five bursts of four pulses delivered at 100 Hz) lasted for up to 3 h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15x4) or three TBS (15x4) 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 (5x4) in young adults was fully dependent on N-methyl D-aspartate (NMDA) receptor and calmodulin-dependent protein kinase II (CaMKII) activity but independent of protein kinase A (PKA) or protein kinase C (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 Ser₈₃₁ (CaMKII target) but not GluA1 Ser₈₄₅ (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser₄₃₈ (CaMKII target) but not at Thr₆₀₂ or Thr₆₀₇ (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC, or kinases of the ERK/MAPK family although important modulators of TBS (5x4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus.

Keywords: AMPA receptors; CaMKII; GABA receptors; Kv4.2; hippocampal CA1; theta burst LTP.