Activation of ryanodine receptors is required for PKA‐mediated downregulation of A‐type K+ channels in rat hippocampal neurons

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Cellular mechanisms for memory and learning functions in mammalian brains are predominantly based on synapse‐specific modifications, such as long‐term potentiation (LTP) or depression (LTD; Hebb 1949; Maren and Baudry, 1995; Yang et al., 2014). These physiological changes in synapses can serve as potent models that initially trigger memory formation at the cellular level and are often accompanied by changes in intrinsic excitability (IE) in the soma (Aizenman and Linden, 2000; Daoudal and Debanne, 2003; Kim and Linden, 2007; Oh et al., 2003; Xu et al., 2005; Zhang and Linden, 2003). Therefore, the verification of mechanical or functional links between local synaptic plasticity and IE is necessary for explaining memory formation and stabilization.
Potassium outflow through various voltage‐dependent K+ channels is a crucial factor for regulating synaptic plasticity and determines the level and pattern of neuronal outputs with a given set of inputs. In CA1 hippocampal neurons, the total outward K+ current consists of a transient or rapidly inactivating current (known as A‐type [IA]) and a sustained or slow/non‐inactivating current (Hoffman et al., 1997). Specifically, IA channel internalization from active spines is dominantly dependent on NMDA receptor (NMDAR) activation, which can simultaneously induce GluR1 insertion during the induction of synaptic LTP in hippocampal neurons. Ca2+ influx through NMDARs in an active synapse seems to be locally restricted and insufficient for activating kinases and auxiliary proteins related to channel trafficking, but the rapid Ca2+‐dependent internalization of IA channels has been observed throughout an entire neuron (Hammond et al., 2008; Jung and Hoffman, 2009; Kim et al., 2007). According to microscopic images and electrophysiological data provided by those reports, LTP‐induced internalization of IA channels was widely observed in spines, dendrites, and somatic membranes. Because LTP induction in hippocampi is dependent on the activation of synaptic NMDARs, the somatic internalization of IA channels suggests that even though they are locally restricted, synaptic events may directly regulate somatic excitability. However, it is not obvious how local cellular signaling for synaptic plasticity can induce widespread IA internalization throughout an entire neuron and subsequently affect somatic excitability.
In CA1 neurons, Ca2+ influx through synaptic NMDARs contributes to the enhancement of synaptic expression of AMPA receptors (AMPARs) and then induces LTP (Disterhoft and Oh, 2006). In particular, the amount of Ca2+ entering synaptic sites determines the potentiation level and duration of LTP, indicating the powerful role of synaptic NMDARs (Malinow and Malenka, 2002; Nicoll and Malenka, 1999). With NMDAR‐dependent Ca2+ influx, ryanodine receptors (RyRs) and inositol‐tri‐phosphate receptors (IP3Rs) in the endoplasmic reticulum (ER) are also involved in NMDA‐dependent synaptic modification of both LTP and LTD (Nishiyama et al., 2000; Zhang et al., 2015). Furthermore, because synaptic NMDAR activation increases cytosolic Ca2+ levels by opening RyRs and IP3Rs, opening Ca2+ stores may be a considerable dominant factor for triggering widespread cellular events following LTP induction (Emptage et al., 1999; Nishiyama et al., 2000; Popescu et al., 2010). Although it is still unclear which ER receptor is more dominant in regulating Ca2+ signaling and inducing synaptic plasticity, a number of studies are focusing on the different gating properties between RyRs and IP3R and their cellular distribution for demonstrating LTP‐mediated signaling. In particular, because RyRs are locally expressed in dendritic spines and induce Ca2+ spark flows from the ER, these receptors seem to be dominantly required for inducing synaptic potentiation (Miyazaki and Ross, 2013; Yuan et al., 2016). These studies specifically demonstrate that RyR2, one isoform of RyRs, is a critical factor for the induction of synaptic LTP in hippocampal neurons. Unlike RyRs, IP3Rs tend to attenuate LTP and facilitate LTD (Taufiq et al., 2005; Yamazaki et al., 2011).
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