Effects of M1 and M4 activation on excitatory synaptic transmission in CA1

Abstract

Hippocampal networks are particularly susceptible to dysfunction in many neurodegenerative diseases and neuropsychiatric disorders including Alzheimer's disease, Lewy body dementia, and schizophrenia. CA1, a major output region of the hippocampus, receives glutamatergic input from both hippocampal CA3 and entorhinal cortex, via the Schaffer collateral (SC) and temporoammonic (TA) pathways, respectively. SC and TA inputs to CA1 are thought to be differentially involved in the retrieval of previously stored memories versus the encoding of novel information, and switching between these two crucial hippocampal functions is thought to critically depend on acetylcholine (ACh) acting at muscarinic receptors. In this study, we aimed to determine the roles of specific subtypes of muscarinic receptors in mediating the neuromodulatory effects of ACh on glutamatergic synaptic transmission in the SC and TA pathways of CA1. Using selective pharmacological activation of M1 or M4 receptors along with extracellular and intracellular electrophysiology recordings from adult rat hippocampal slices, we demonstrate that activation of M1 receptors increases spontaneous spike rates of neuronal ensembles in CA1 and increases the intrinsic excitability of pyramidal neurons and interneurons. Selective activation of M4 receptors inhibits glutamate release in the SC pathway, while leaving synaptic transmission in the TA pathway comparatively intact. These results suggest specific mechanisms by which M1 and M4 activation may normalize CA1 circuit activity following disruptions of signaling that accompany neurodegenerative dementias or neuropsychiatric disorders. These findings are of particular interest in light of clinical findings that xanomeline, an M1/M4 preferring agonist, was able to improve cognitive and behavioral symptoms in patients with Alzheimer's disease or schizophrenia.

Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

“…We further extended previous studies by demonstrating that suppression of SLM inputs by ACh release was mediated by muscarinic M2 receptor activation. These latter findings were consistent with observations from a recent study that suggest that presynaptic inhibition at synapses in the SLM was not mediated by M4 muscarinic receptors (Thorn et al 2017). Therefore, our data confirms and extends observation made by previous studies and suggest that ACh release from MS/DBB cholinergic terminals results in presynaptic inhibition of inputs in the SLM via the activation of M2 receptors.…”

“…Our studies extended these studies by being the first to investigate modulation of synaptically released ACh on excitatory afferents in SLM. Consistent with studies utilizing bath application of cholinergic agonists, we observed that ACh release suppressed excitatory inputs in SLM (M. Hasselmo and Schnell 1994;Thorn et al 2017). Furthermore, ACh release appeared to act presynaptically as the inhibition of afferents in SLM was accompanied by an increase in the PPR, which is frequently used to determine presynaptic function.…”

“…A small number of studies have investigated cholinergic receptor modulation of excitatory inputs in the SLM of hippocampal CA1 (M. Hasselmo and Schnell 1994;Thorn et al 2017). Our studies extended these studies by being the first to investigate modulation of synaptically released ACh on excitatory afferents in SLM.…”

“…Previous studies have reported that activation of presynaptic muscarinic receptors causes inhibition of the SC and TA inputs (Fernández de Sevilla and Buño 2003;M. Hasselmo and Schnell 1994;Thorn et al 2017). Alternatively, activation of nicotinic receptors has been shown to enhance glutamate release and reduce PPR in the SC (Maggi et al 2003).…”

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

“…Perhaps counter-intuitively, acetylcholine inhibits both TA and SC glutamatergic excitatory transmission in CA1. In the SC pathway this occurs via presynaptic muscarinic M 4 receptors but the identity of the receptors mediating depression at the TA pathway is unclear (Dasari and Gulledge, 2011; Goswamee and McQuiston, 2019; Thorn et al, 2017). The anatomically segregated targeting of TA and SC inputs to distal and more proximal dendritic locations on…”