Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation

Abstract

Spike timing-dependent synaptic plasticity (STDP) serves as a key cellular correlate of associative learning, which is facilitated by elevated attentional and emotional states involving activation of adrenergic signaling. At cellular levels, adrenergic signaling increases dendrite excitability, but the underlying mechanisms remain elusive. Here we show that activation of β2-adrenoceptors promoted STD long-term synaptic potentiation at mouse hippocampal excitatory synapses by inactivating dendritic Kv1.1-containing potassium channels, which increased dendrite excitability and facilitated dendritic propagation of postsynaptic depolarization, potentially improving co-incidental activation of pre- and postsynaptic terminals. We further demonstrate that adrenergic modulation of Kv1.1 was mediated by the signaling scaffold SAP97, which, through direct protein-protein interactions, escorts β2-signaling to remove Kv1.1 from the dendrite surface. These results reveal a mechanism through which the postsynaptic signaling scaffolds bridge the aroused brain state to promote induction of synaptic plasticity and potentially to enhance spike timing and memory encoding.

Cooperative CRF and α1 Adrenergic Signaling in the VTA Promotes NMDA Plasticity and Drives Social Stress Enhancement of Cocaine Conditioning

“…While previous studies reporting CRF/NE-induced enhancement of AMPA plasticity outside of the VTA have mostly focused on regulation of neuronal excitability ( Blank et al, 2002 ; Liu et al, 2017 ) or postsynaptic AMPA receptors ( Hu et al, 2007 ; Seol et al, 2007 ), our study implicates CRF/NE effects on a Ca 2+ -dependent induction process as the mechanism for enhancement or facilitation of NMDA plasticity. NE acting on β-adrenergic receptors (βARs) has been shown to enhance spike-timing-dependent plasticity in the hippocampus by regulating the timing of pre- and postsynaptic spikes ( Lin et al, 2003 ; Seol et al, 2007 ) or the number of postsynaptic spikes ( Liu et al, 2017 ). The present study suggests that NE acting on α1ARs to generate IP 3 , together with CRFR2 amplifying this α1AR effect, promotes LTP-NMDA in VTA DA neurons, potentially enabling conditioning to subthreshold doses of cocaine.…”

Neuromodulation of hippocampal long-term synaptic plasticity

“…Noradrenaline activates α1-adrenergic, α2-adrenergic and β-adrenergic GPCRs with the β receptors, signalling via Gs and cAMP, exerting the major impact on LTP and LTD. Noradrenaline facilitates LTP in CA1 [ 33 , 34 , 35 ] but there is also strong evidence for a role enhancing LTP and LTD within dentate gyrus — CA3 circuits [ 36 , 37 ] which links to evidence of increased density of noradrenergic fibers in these regions [ 38 •• ]. There are several proposed mechanisms for the facilitation of LTP and LTD ( Figure 2 ).…”

“…There are several proposed mechanisms for the facilitation of LTP and LTD ( Figure 2 ). Similar to acetylcholine, noradrenaline enhances NMDAR activity by inhibiting potassium channels including Kv1.1, Kv4.2 and SK channels [ 33 , 39 , 40 ] and by direct phosphorylation of NMDARs by PKA [ 41 ]. Compared to acetylcholine, there is a paucity of data on the actions of noradrenaline on inhibitory interneuron populations, so this area remains to be fully explored.…”

Norepinephrine controls the gain of the inhibitory circuit in the cerebellar input layer

“…Our results suggest that NE has rather subtle effects on excitatory synaptic drive onto GoCs and on GoC-mediated inhibition onto GCs. This is surprising given its widespread effects on synaptic transmission: NE downregulates synaptic transmission (Carey and Regehr, 2009;Delaney et al, 2007;Ohshima et al, 2017; H. X. and synaptic plasticity (Bear and Singer, 1986;Liu et al, 2017;Pettigrew and Kasamatsu, 1978) in different brain areas via presynaptic modulation of release probability (for review see: (Sara, 2009)). In the cerebellum, α2-adrenergic receptor activation at climbing fiber to Purkinje cell synapses inhibits excitatory synaptic transmission via a decrease in presynaptic release and impacts the induction of associative plasticity (Carey and Regehr, 2009).…”