PhD Scientific Days 2024

Neurosciences

Cholinergic Regulation of Dendritic Ca2+ Spikes Controls Firing Mode of Hippocampal CA3 Pyramidal Neurons

Text of the abstract

The hippocampus plays a critical role in spatial and contextual memory processes. Hippocampal pyramidal cells (PCs) typically fire when an animal is at a certain location in the environment, and they often exhibit complex spike bursts (CSBs) that are driven by regenerative dendritic Ca2+ spikes (called plateau potentials). CSBs can induce rapid synaptic plasticity and the formation of new place fields in CA1PCs. CSBs are also present in CA3PCs, with particularly prolonged duration. However, the dendritic mechanisms behind these long-lasting events in CA3PCs remain unclear.
In previous work we have found large heterogeneity among CA3PCs in CSB prevalence and in dendritic Ca2+ spikes kinetics, linked to morpho-topographical properties. While many CA3PCs express long (~50 ms) compound Ca2+ spikes, some display unusually short (few ms) spikes, not supporting sustained CSB firing. This raised the question whether specific conditions are required to gate the ability of these CA3PCs to fire prolonged plateaus. Acetylcholine (ACh) influences dendritic integrative functions, memory processes and affects ion channels including those mediating and shaping Ca2+ spikes in CA3PCs, leading us to explore cholinergic regulation of Ca2+ spikes.

We aimed to examine the effect of cholinergic activity on Ca2+ spikes and CSB firing in rat CA3PCs.

We used patch-clamp recordings and two-photon microscopy in acute rat brain slices, combined with pharmacological or optogenetic interrogation of cholinergic neuromodulation.

We found that the ACh receptor agonist carbachol drastically transformed short-duration Ca2+ spikes into long-lasting forms and facilitated long-duration CSBs. In contrast, Ach receptor blockade did not affect Ca2+ spikes, suggesting that the spike heterogeneity is not due to variable cholinergic tone in the slice. Optogenetic stimulation of cholinergic axons in transgenic mice (ChAT-Cre/Ai32) increased CSB rate and duration.

Our results suggest that cholinergic neuromodulation gates the ability of CA3PCs with short-duration Ca2+ spikes to generate sustained plateau potentials. This state-dependent dendritic mechanism may contribute to memory encoding and retrieval processes.

This work was funded by the ERC (CoG #771849), the NAP3.0 Program, the HHMI (ISR grant #55008740), the NKFIH (#K-124824) and the ÚNKP (#ÚNKP-23-3-II-SE-89).