BEHAVIOURAL TIMESCALE SYNAPTIC PLASTICITY REQUIRES CATECHOLAMINERGIC MODULATION

Behavioural timescale synaptic plasticity (BTSP) is a recently identified form of hippocampal synaptic modification proposed as a cellular explanation for the rapid formation of place fields during spatial learning. BTSP induction is non-Hebbian and operates over seconds, differing from spike-timing-dependent plasticity, which operates on millisecond timescales. In CA1 pyramidal neurons, BTSP is triggered by large dendritic plateau potentials, resulting in robust synaptic changes of temporally proximal inputs enabling rapid, one-shot learning during behaviour. While the cellular and circuit mechanisms underlying BTSP have begun to be elucidated, little is known about how neuromodulatory systems regulate its induction and temporal window. Using whole-cell patch clamp electrophysiology techniques in acute hippocampal mouse brain slices, we show that BTSP requires catecholaminergic modulation during induction for robust expression of synaptic potentiation at Schaffer Collateral-CA1 pyramidal cell synapses. Compared to control levels of potentiation (+140 ± 18%; n=7), co-application of antagonists at both dopaminergic (SCH-23390 and Sulpiride) and beta-adrenergic (Propranolol) receptors completely blocks BTSP (-16 ± 6%; n=6) (p=0.001); however, application of each individually did not. Considering shared downstream signalling pathways, we found a requirement for protein kinase A (PKA) using PKA inhibitor fragment (6-22) amide, which again significantly reduced potentiation (+14 ± 10%; n=6) (p=0.001) (mean ± SEM), suggesting the effect may be mediated by Gαs-protein-coupled receptor signalling. PKA involvement indicates an underlying mechanism of BTSP distinct from that of conventional, exclusively Calcium/calmodulin-dependent protein kinase II-dependent long-term potentiation. Discovering the underlying mechanisms and neuromodulatory requirements of BTSP may help discern the function of this synaptic learning rule during behaviour.