β-adrenergic receptor activation modulates the induction of complex spike burst-dependent LTP by regulating multiple forms of heterosynaptic plasticity

Abstract

The modulatory neurotransmitter norepinephrine and activation of {beta}-adrenergic receptors ({beta}-ARs) has a crucial role in hippocampus-dependent forms of learning. Although {beta}-AR activation also facilitates the induction of Hebbian LTP at excitatory synapses in the hippocampus, recent findings indicate that a non-Hebbian form of synaptic plasticity, known as behavioral timescale synaptic plasticity (BTSP), underlies hippocampus-dependent spatial learning. Because little is known about the role of noradrenergic signaling in BTSP, I examined the effects of the {beta}-AR activation on a BTSP-like, complex spike (CS) burst-dependent form of LTP induced by theta-pulse stimulation (TPS) protocols in the CA1 region of mouse hippocampal slices. I find that {beta}-AR activation not only enhances the homosynaptic potentiation of synaptic transmission induced by TPS but also regulates how synapses interact during the induction of CS burst-dependent LTP. The ability of synapses to interact in a cooperative fashion to undergo CS burst-dependent LTP, which is mediated by a heterosynaptic facilitation of EPSP-evoked CS bursting induced by brief trains of TPS, was enhanced by {beta}-AR activation. Moreover, unlike conventional Hebbian LTP, where cooperative LTP induction requires near synchronous coactivation of synapses, {beta}-AR activation enabled the induction of CS burst-dependent LTP by cooperative interactions between synapses activated up to ten seconds apart. {beta}-AR activation also enhanced a potent form of synaptic competition that emerges during longer trains of TPS. This effect of {beta}-AR activation is mediated by a CS burst-dependent form of heterosynaptic depression and produces an unusual, bidirectional modulation of LTP induction where the {beta}-AR-mediated facilitation of homosynaptic LTP induction produces a heterosynaptic suppression of LTP induction at other synapses. Together, these findings indicate that {beta}-AR activation regulates fundamental properties of postsynaptic burst-dependent plasticity rules by modulating multiple forms of heterosynaptic plasticity.