Endogenous inhibition of hippocampal LTD and depotentiation by vasoactive intestinal peptide VPAC1 receptors.
Cunha-Reis. Diana D; Aidil-Carvalho. Maria de Fatima Mde F; Ribeiro. Joaquim A JA
Key Findings
- Endogenous VIP suppresses hippocampal LTD and depotentiation via VPAC1 receptors.
- Blocking VPAC1 with the peptide antagonist GRF‑1‑29 (Ac‑Tyr(1), D‑Phe(2) GRF 1‑29) enhances LTD and depotentiation.
- The enhancement involves GABAergic transmission and is not seen with VPAC2 blockade.
Practical Outcomes
- For now, the findings are mostly mechanistic and don’t translate into a ready‑to‑use protocol. They suggest that drugs or supplements that inhibit VPAC1 signaling might improve cognitive flexibility, but human studies, dosing information, and safety data are still needed before biohackers can apply this.
Summary
The study shows that a natural brain chemical called VIP normally blocks certain types of learning‑related brain changes (LTD and depotentiation) by acting on VPAC1 receptors. When a drug that blocks these VPAC1 receptors (the peptide GRF‑1‑29) is added, those brain changes become stronger, suggesting that reducing VIP signaling could boost learning flexibility. The effect also depends on GABA, another brain messenger.
Abstract
Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal-dependent learning in rodents. Homosynaptic long-term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low-frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac-Tyr(1) , D-Phe(2) GRF (1-29), and the selective VPAC1 receptor antagonist, PG 97-269, but not the selective VPAC2 receptor antagonist, PG 99-465. This action was mimicked by an anti-VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase-activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6-38) enhanced depotentiation, but not LTD. VPAC1 receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABAA antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC1 receptor-mediated mechanisms and suggest that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC1 receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy.
Study Information
pubmed
2014
2014-07-07T00:00:00.000Z
10.1002/hipo.22316
21
54