Heterosynaptic Plasticity of the Visuo-auditory Projection Requires Cholecystokinin released from Entorhinal Cortex Afferents

Abstract

The entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex, using optogenetics of dual pathways. High-frequency laser stimulation (HFLS) of the visuo-auditory projection did not induce long-term potentiation (LTP). However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFLS of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that CCK expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the pre-synaptic input arrived 200 ms before post-synaptic firing, even after just five trials of pairing. Behaviorally, inhibition of CCK signaling blocked the generation of associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.

Cholecystokinin modulates age-dependent Thalamocortical Neuroplasticity

“…Previous studies have demonstrated that both exogenous and endogenous CCK can induce synaptic plasticity in different neural pathways [24][25][26][27][28][29] . HFS of entorhino-neocortical terminals triggers the release of CCK, thereby facilitating the formation of cortical LTP 25,26 .…”

“…However, it is important to note that the changes observed in ACx may not exclusively result from the alterations at thalamocortical synapses. Heterosynaptic release of CCK from entorhinoneocortical projections has been implicated in modulating corticocortical plasticity and associative memory 25,26,28 . Similarly, thalamocortical projection may also influence intracortical plasticity.…”

“…Moreover, highfrequency stimulation (HFS) has been shown to induce cortical LTP in a manner that is dependent on CCK 25,26 . HFS of entorhino-neocortical pathway triggers CCK release from its terminals in the ACx, subsequently leading to cortico-cortical LTP and the formation of soundsound associative memory 25,26 , as well as visuoauditory associative memory 27,28 .…”