Recurring Cholinergic Inputs Induce Local Hippocampal Plasticity through Feedforward Disinhibition.

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that recurring cholinergic activation of α7 nACh receptors expressed in oriens-lacunosum-moleculare (OLMα2) interneurons can directly induce LTP in Schaffer collateral (SC)-CA1 synapses. Here, we pair in vitro studies with biophysically based modeling to uncover the underlying mechanisms. According to our model, α7 nAChR activation increases OLM GABAergic activity. This results in the inhibition of the fast-spiking interneurons that provide feedforward inhibition onto CA1 pyramidal neurons. This disinhibition, paired with tightly timed SC stimulation, can induce potentiation at the excitatory synapses of CA1 pyramidal neurons. Our work details the role of cholinergic modulation in disinhibition-induced hippocampal plasticity. It relates the timing of cholinergic pairing found experimentally in previous studies with the timing between disinhibition and hippocampal stimulation necessary to induce potentiation and suggests the dynamics of the involved interneurons play a crucial role in determining this timing.Significance StatementWe use a combination of experiments and mechanistic modeling to uncover the key role for cholinergic neuromodulation of feedforward disinhibitory circuits in regulating hippocampal plasticity. We found that cholinergic activation of α7 nAChR on α7 nACh receptors expressed in oriens-lacunosum-moleculare interneurons, when tightly paired with stimulation of the Schaffer collaterals, can cancel feedforward inhibition onto CA1 pyramidal cells, enabling the potentiation of the SC-CA1 synapse. Our work details how cholinergic action on GABAergic interneurons can tightly regulate the excitability and plasticity of the hippocampal network, unraveling the intricate interplay of the hierarchal inhibitory circuitry and cholinergic neuromodulation as a mechanism for hippocampal plasticity.