Behavioral timescale synaptic plasticity in the hippocampus creates non-spatial representations during learning and is modulated by entorhinal inputs.

Behavioral timescale synaptic plasticity (BTSP) is a form of synaptic potentiation where a single plateau potential in hippocampal neurons forms a place field during spatial learning. We asked whether BTSP can also form non-spatial responses in the hippocampus and what roles the medial and lateral entorhinal cortex (MEC and LEC) play in driving non-spatial BTSP. Two-photon calcium imaging of dorsal CA1 neurons while mice performed an odor-cued working memory task revealed plateau-like events which formed stable odor-specific responses. These BTSP-like events were much more frequent during the first day of task learning, suggesting that BTSP may be important for early learning. Strong single-neuron stimulation through holographic optogenetics induced plateau-like events and subsequent odor-fields, causally linking BTSP with non-spatial representations. MEC chemogenetic inhibition reduced the frequency of plateau-like events, whereas LEC inhibition reduced potentiation and field-induction probability. Calcium imaging of LEC and MEC temporammonic CA1 projections revealed that MEC axons were more strongly activated by odor presentations, while LEC axons were more odor-selective, further confirming the role of MEC in driving plateau-like events and LEC in relaying odor-specific information. Altogether, odor-specific information from LEC and strong odor-timed activity from MEC are crucial for driving BTSP in CA1, which is a synaptic plasticity mechanism for generation of both spatial and non-spatial responses in the hippocampus.