High-frequency Activation of GABAergic Cholecystokinin Neurons Potentiates their Inhibition and Induces Long-term Depression in the Hippocampus

Abstract

In the hippocampus, long-term potentiation (LTP) and long-term depression (LTD) are two major forms of activity-dependent plasticity that serve as the physiological foundation for multiple cognitive functions, such as encoding and storage of specific associative memories. The commonly accepted mechanisms are mediated by the postsynaptic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs).

Our previous studies demonstrated that N-methyl-D-aspartate receptors (NMDARs) trigger the release of cholecystokinin (CCK) from the synaptic terminals of entorhinal neurons and induce LTP in the neocortex. LTP induction was blocked using CCK receptor antagonist. Furthermore, 1 Hz electrical stimulation (ES) with local infusion of CCK produced LTP in the auditory cortex.

In this study, we investigated whether CCK⁺ terminals in the hippocampal CA1 projected from the entorhinal cortex (EC) mediate LTP formation. Viral optogenetic tools and transgenic mice were utilised to specifically trace the Schaffer collateral (SC) and the temporoammonic (TA)-pathways in the CA1. We failed to induce LTP in either the SC or TA-pathway after high-frequency (HF) laser stimulation. However, pairing 1 Hz ES or laser stimulation of the SC-pathway with HF activated TA-pathway produced LTP in the SC-pathway. These results indicate that HF activation of EC→CA1 CCK⁺ projections enables the heterosynaptic plasticity of the SC-pathway.

LTD is another crucial form of plasticity which supports multiple neuronal functions. Endocytosis of AMPARs on postsynaptic membranes triggered by “anti-Hebbian” neural activities or prolonged low-frequency activation has attracted a great deal of interest in explaining the cellular mechanisms of LTD. In contrast to the conventional view, we investigated whether hippocampal LTD can be triggered by changes in local inhibitory synaptic strength.

Here, we observed that following high-frequency activation, CCK⁺ interneurons potentiated their inhibitory effect on both the SC and TA-pathway. However, low-frequency stimulation (LFS) of CCK⁺ interneurons failed to cause any long-term changes in the inhibitory effect on local circuits. These results suggest that intensive activation of CCK⁺ interneurons in the hippocampus results in inhibitory long-term potentiation. Next, we found that hippocampal LTD was triggered by high-frequency activation of CCK⁺ interneurons, while LFS was unable to induce LTD.

CCK, one of the most abundant neuropeptides in the central nervous system, is shown to relate with multiple neuronal functions and strongly associate with synaptic plasticity. We investigated whether the lack of endogenous CCK could influence LTD induction by classical ES protocol. And we found that prolonged LFS failed to induce hippocampal LTD in CCK knockout mice, whereas wild-type mice showed intact LTD. Furthermore, viral knockdown of endogenous CCK in the hippocampus blocked LTD induction; however, LTD was produced in the control group. These results indicate a causal link between endogenous CCK of GABAergic interneurons and hippocampal LTD induction.

To conclude, the results of the present study provide more evidence to support the distinct roles of the two sources of CCK in LTP and LTD induction.

Date of Award	2 Jul 2021
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Jufang HE (Supervisor) & Robert OSWALD (External Co-Supervisor)