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

Abstract

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations by facilitating synaptic plasticity. It is also proposed that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3, but this influential theory has not been directly tested. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, greater depression of feedforward inhibition from entorhinal cortex results in an overall enhancement of excitatory-inhibitory balance and CA1 activation. Underpinning the prioritisation of entorhinal inputs, entorhinal and CA3 pathways engage distinct feedforward interneuron subpopulations and depression is mediated differentially by presynaptic muscarinic M3 and M4 receptors respectively. These mechanisms enable acetylcholine to prioritise novel information inputs to CA1 during memory formation and suggest selective muscarinic targets for therapeutic intervention.

Differential regulation of prelimbic and thalamic transmission to the basolateral amygdala by acetylcholine receptors

“…This disparity was caused by differential regulation of transmitter release by M4 and M3 receptors at the two inputs. These findings are consistent with growing evidence of highly specific localization of muscarinic receptor types to distinct neural pathways in the brain (Gil et al, 1997; Palacios-Filardo et al, 2021). The finding that M4 receptors regulate PL input is the first demonstration of presynaptic inhibition by M4 receptors in the BLa and builds on prior work showing presynaptic regulation by M4 receptors in other brain regions (Dasari and Gulledge, 2011; Pancani et al, 2014; Yang et al, 2020; Palacios-Filardo et al, 2021).…”

“…These findings are consistent with growing evidence of highly specific localization of muscarinic receptor types to distinct neural pathways in the brain (Gil et al, 1997; Palacios-Filardo et al, 2021). The finding that M4 receptors regulate PL input is the first demonstration of presynaptic inhibition by M4 receptors in the BLa and builds on prior work showing presynaptic regulation by M4 receptors in other brain regions (Dasari and Gulledge, 2011; Pancani et al, 2014; Yang et al, 2020; Palacios-Filardo et al, 2021). Inhibition by M4 receptors was likely mediated by a suppression of presynaptic N- and P-type voltage-gated calcium channels through a Gi/o protein-dependent mechanism (Hille, 1994; Howe and Surmeier, 1995; Yan and Surmeier, 1996).…”

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

“…The observed differences between exogenous applications of acetylcholine and noradrenaline will likely be accentuated under endogenous neuromodulator release. The concentration of CCh used (5 μM) produces effects in the hippocampus that closely match those caused by optogenetically induced release so endogenous acetylcholine release would likely have similar effects to those we report here [ 98 ] and the timecourse of cholinergic receptor activation produced by bath application of CCh is a reasonable approximation of tonic levels of acetylcholine release in vivo [ 15 , 99 ]. The concentration of noradrenaline used (20 μM) is somewhat higher than that thought to be evoked by endogenous release in CA1 [ 31 , 100 ] but there is a higher density of noradrenergic fibers in CA3 than CA1 and more direct synaptic targeting [ 16 , 101 , 102 ] making it likely that the effective concentration of noradrenaline in CA3 is likely in the micromolar range but lower than 20 μM.…”

Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit

“…In vivo , LEC-driven dendritic spikes may therefore serve to assign contextual salience to sensory cues in the environment. This could be especially effective if dendritic excitability and signal propagation is boosted by the co-activation of long-range glutamatergic and GABAergic LEC inputs or other brain state-dependent neuromodulatory signals (Ito and Schuman, 2007; Lee et al, 2021; Lovett-Barron et al, 2014; Palacios-Filardo et al, 2021).…”