Abstract
Long-term potentiation (LTP) is a highly studied phenomenon yet the essential vs. modulatory transduction and GABAergic pathways involved in LTP elicited by theta-burst stimulation (TBS) in the CA1 area of the hippocampus are still unclear, due to the use of different TBS intensities and patterns or of different rodent/cellular models. We now characterized the essential transduction and GABAergic pathways in mild TBS-induced LTP in the CA1 area of the rat hippocampus. LTP induced by TBS (5×4) (5 bursts of 4 pulses delivered at 100Hz) lasted for up to 3h and was increasingly greater 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) was fully dependent on NMDA receptor and CaMKII activity but independent on PKA or PKC activity. In addition, it was partially dependent on GABAB receptor activation and was potentiated by GABAA 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 (targeted by CaMKII) but not at Thr602 or Thr607 (ERK/MAPK pathway). This suggests that cellular kinases like PKA, PKC or kinases of the ERK/MAPK family although important modulators of TBS (5×4)-induced LTP are not essential for its expression in the CA1 area of the hippocampus.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interests: The authors have no conflict of interests to publication of this paper.
NC Rodrigues: formal analysis and methodology; A Silva-Cruz: formal analysis and methodology; A Caulino-Rocha: formal analysis and writing - review and editing; A Bento-Oliveira: methodology; JA Ribeiro: resources, supervision and writing – review and editing and D Cunha-Reis: formal analysis and methodology, resources, supervision, funding acquisition, project administration, and writing – original draft, review and editing.
Funding: This work was supported national and international funding managed by Fundação para a Ciência e a Tecnologia (FCT, IP), Portugal. Grants: UIDB/04046/2020 and UIDP/04046/2020 centre grants (to BioISI) and research grants PTDC/SAU-NEU/103639/2008 and FCT/POCTI (PTDC/SAUPUB/28311/2017) EPIRaft grant (to DC-R). Fellowships: SFRH/BPD/34661/2007 and SFRH/BPD/81358/2011 to DCR and Researcher contract: Norma Transitória - DL57/2016/CP1479/CT0044 to DCR. Funding sources made no contribution to the writing, research plan and decision to publish this paper.