Acetylcholine disinhibits hippocampal circuits to enable rapid formation of overlapping memory ensembles

Abstract

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. Since CA3 network capacity is finite, a mechanism for enhancing memory encoding during important events would ensure greater efficiency, but the salient signal that might determine this memory selectivity filter is unknown. Using experimental and computational methods we show that the cholinergic system can operate as a memory selectivity filter by combining 3 separate mechanisms: disinhibition of feed-forward mossy fiber inhibition enables synaptic plasticity at CA3-CA3 recurrent synapses; Increasing cellular excitability lowers the threshold for ensemble formation; Reduction of overall CA3-CA3 recurrent synapse strength allows for an increase in overlap between ensembles. Thus, we show that acetylcholine release enables the selective encoding of salient high-density episodic memories in the hippocampus.