Abstract
In hippocampal CA1, muscarinic acetylcholine (ACh) receptor (mAChR) activation via exogenous application of cholinergic agonists has been shown to presynaptically inhibit Schaffer collateral (SC) glutamatergic inputs in stratum radiatum (SR), and temporoammonic (TA) and thalamic nucleus reuniens (RE) glutamatergic inputs in stratum lacunosum-moleculare (SLM). However, steady-state uniform mAChR activation may not mimic the effect of ACh release in an intact hippocampal network. To more accurately examine the effect of ACh release on glutamatergic synaptic efficacy, we measured electrically evoked synaptic responses in CA1 pyramidal cells (PCs) following the optogenetic release of ACh in genetically modified mouse brain slices. The ratio of synaptic amplitudes in response to paired-pulse SR stimulation (stimulus 2/stimulus 1) was significantly reduced by the optogenetic release of ACh, consistent with a postsynaptic decrease in synaptic efficacy. The effect of ACh release was blocked by the M3 receptor antagonist 4-DAMP, the GABAB receptor antagonist CGP 52432, inclusion of GDP-β-S, cesium, QX314 in the intracellular patch clamp solution, or extracellular barium. These observations suggest that ACh release decreased SC synaptic transmission through an M3 muscarinic receptor-mediated increase in inhibitory interneuron excitability, which activate GABAB receptors and inwardly rectifying potassium channels on CA1 pyramidal cells. In contrast, the ratio of synaptic amplitudes in response to paired-pulse stimulation in the SLM was increased by ACh release, consistent with presynaptic inhibition. ACh-mediated effects in SLM were blocked by the M2 receptor antagonist AF-DX 116, presumably located on presynaptic terminals. Therefore, our data indicate that ACh release differentially modulates excitatory inputs in SR and SLM of CA1 through different cellular and network mechanisms.
Highlights
Medial septum and diagonal band of Broca complex (MS/DBB) cholinergic neurons project to the hippocampus where they influence attention, learning, and memory (Hasselmo, 2006), and synaptic plasticity (Zhenglin and Yakel, 2011)
With resting membrane potential near −60 mV, 600 ms duration light-evoked responses were often accompanied by 1–2 action potentials (APs) that occurred near the beginning of the light pulse
Our data have shown that optogenetically released ACh in mouse hippocampal slices differentially inhibited glutamatergic synaptic transmission onto CA1 pyramidal cells (PCs) depending on the input
Summary
Medial septum and diagonal band of Broca complex (MS/DBB) cholinergic neurons project to the hippocampus where they influence attention, learning, and memory (Hasselmo, 2006), and synaptic plasticity (Zhenglin and Yakel, 2011). A proportionately larger presynaptic muscarinic receptor-mediated inhibition has been observed in the SC pathway of SR compared to inhibition of inputs located in the SLM (Hasselmo and Schnell, 1994). These studies were conducted using exogenous uniform activation of muscarinic receptors in rat brain slices. Muscarinic receptors located on different subsets of presynaptic glutamatergic terminals may be exposed to different concentrations of acetylcholine following release from MS/DBB terminals This would impact the magnitude of cholinergic presynaptic inhibition following the release of ACh from synaptic terminals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
