Cholinergic Stimulation Modulates the Functional Composition of CA3 Cell Types in the Hippocampus

TY - JOUR

T1 - Cholinergic Stimulation Modulates the Functional Composition of CA3 Cell Types in the Hippocampus

AU - Puhl, Christopher Jon

AU - Wefelmeyer, Winnie

AU - Burrone, Juan

N1 - Funding Information: This work was supported in whole, or in part, by Wellcome Trust 095589/Z/11/Z and 215508/Z/19/Z. This work was also supported by ERC Starter Grant 282047 and Biotechnology and Biological Sciences Research Council Project Grant BB/S000526/1 to J.B., and a Medical Research Council studentship to C.J.P. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. We thank Matthew Grub, Guilherme Neves, Rachel Jackson, and Mala Shah for useful feedback and comments on this manuscript. The authors declare no competing financial interests. Publisher Copyright: © 2023 the authors.

PY - 2023/7/5

Y1 - 2023/7/5

N2 - The functional heterogeneity of hippocampal CA3 pyramidal neurons has emerged as a key aspect of circuit function. Here, we explored the effects of long-term cholinergic activity on the functional heterogeneity of CA3 pyramidal neurons in organotypic slices obtained from male rat brains. Application of agonists to either AChRs generally, or mAChRs specifically, induced robust increases in network activity in the low-gamma range. Prolonged AChR stimulation for 48 h uncovered a population of hyperadapting CA3 pyramidal neurons that typically fired a single, early action potential in response to current injection. Although these neurons were present in control networks, their proportions were dramatically increased following long-term cholinergic activity. Characterized by the presence of a strong M-current, the hyperadaptation phenotype was abolished by acute application of either M-channel antagonists or the reapplication of AChR agonists. We conclude that long-term mAChR activation modulates the intrinsic excitability of a subset of CA3 pyramidal cells, uncovering a highly plastic cohort of neurons that are sensitive to chronic ACh modulation. Our findings provide evidence for the activity-dependent plasticity of functional heterogeneity in the hippocampus.

AB - The functional heterogeneity of hippocampal CA3 pyramidal neurons has emerged as a key aspect of circuit function. Here, we explored the effects of long-term cholinergic activity on the functional heterogeneity of CA3 pyramidal neurons in organotypic slices obtained from male rat brains. Application of agonists to either AChRs generally, or mAChRs specifically, induced robust increases in network activity in the low-gamma range. Prolonged AChR stimulation for 48 h uncovered a population of hyperadapting CA3 pyramidal neurons that typically fired a single, early action potential in response to current injection. Although these neurons were present in control networks, their proportions were dramatically increased following long-term cholinergic activity. Characterized by the presence of a strong M-current, the hyperadaptation phenotype was abolished by acute application of either M-channel antagonists or the reapplication of AChR agonists. We conclude that long-term mAChR activation modulates the intrinsic excitability of a subset of CA3 pyramidal cells, uncovering a highly plastic cohort of neurons that are sensitive to chronic ACh modulation. Our findings provide evidence for the activity-dependent plasticity of functional heterogeneity in the hippocampus.

KW - acetylcholine

KW - CA3

KW - excitability

KW - hippocampus

KW - M-current

UR - http://www.scopus.com/inward/record.url?scp=85164235397&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0966-22.2023

DO - 10.1523/JNEUROSCI.0966-22.2023

M3 - Article

C2 - 37277177

AN - SCOPUS:85164235397

SN - 0270-6474

VL - 43

SP - 4972

EP - 4983

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 27

ER -