Kinase-dependent modification of dendritic excitability after long-term potentiation

Center for Learning and Memory, University of Texas at Austin, Austin, TX, USA.
The Journal of Physiology (Impact Factor: 5.04). 12/2008; 587(Pt 1):115-25. DOI: 10.1113/jphysiol.2008.158816
Source: PubMed


Patterns of presynaptic activity properly timed with postsynaptic action potential output can not only increase the strength of synaptic inputs but can also increase the excitability of dendritic branches of adult CA1 pyramidal neurons. Here, we examined the role of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) in the enhancement of dendritic excitability that occurs during theta-burst pairing of presynaptic and postsynaptic firing activity. Using dendritic and somatic whole-cell recordings in rat hippocampal slices, we measured the increase in the amplitude of back-propagating action potentials in the apical dendrite that occurs in parallel with long-term potentiation (LTP) of synaptic inputs. We found that inhibition of the MAPK pathway prevents this enhancement of dendritic excitability using either a weak or strong LTP induction protocol, while synaptic LTP can still be induced by the strong protocol. Both forms of plasticity are blocked by inhibition of PKA and occluded by interfering with cAMP degradation, consistent with a PKA-mediated increase in MAPK activity following induction of LTP. This provides a signalling mechanism for plasticity of dendritic excitability that occurs during neuronal activity and demonstrates the necessity of MAPK activation. Furthermore, this study uncovers an additional contribution of kinase activation to plasticity that may occur during learning.

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Available from: Daniel Johnston, Oct 13, 2015
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    • "p = 0.33, n = 7/7). Then we turned our attention to MEK, which because MAPK cascade is known to be able to integrate coincident signals and to translate the magnitude of signaling into a temporally and spatially graded response [34] and has been previously implicated in learning and memory in behaving animals [35] and shown to be necessary for many forms of synaptic plasticity [34], [36] and dendritic excitability regulation [37] although its precise role is unknown Blocking MEK using 10 uM of U0126 abolished induction of DED (DED = 0.07%±0.3%, p = 0.93). "
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    ABSTRACT: While plasticity is typically associated with persistent modifications of synaptic strengths, recent studies indicated that modulations of dendritic excitability may form the other part of the engram and dynamically affect computational processing and output of neuronal circuits. However it remains unknown whether modulation of dendritic excitability is controlled by synaptic changes or whether it can be distinct from them. Here we report the first observation of the induction of a persistent plastic decrease in dendritic excitability decoupled from synaptic stimulation, which is localized and purely activity-based. In rats this local plasticity decrease is conferred by CamKII mediated phosphorylation of A-type potassium channels upon interaction of a back propagating action potential (bAP) with dendritic depolarization.
    PLoS ONE 01/2014; 9(1):e84086. DOI:10.1371/journal.pone.0084086 · 3.23 Impact Factor
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    • "Our observation that neurons expressing Kv4.2S552A show no significant increase in cycling after stimulation indicates that PKA phosphorylation is also required for activity-dependent Kv4.2 cycling at these sites, which has been observed in neuronal culture (Hammond et al., 2008; Kim et al., 2007). Indeed, LTP can be blocked by inhibition of PKA with a PKA inhibitory peptide fragment (Rosenkranz et al., 2009), suggesting that PKA regulation of Kv4.2 channel cycling may play a role in synaptic plasticity. "
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    ABSTRACT: The heterogeneous expression of voltage-gated channels in dendrites suggests that neurons perform local microdomain computations at different regions. It has been shown that A-type K(+) channels have a nonuniform distribution along the primary apical dendrite in CA1 pyramidal neurons, increasing with distance from the soma. Kv4.2 channels, which are responsible for the somatodendritic A-type K(+) current in CA1 pyramidal neurons, shape local synaptic input, and regulate the back-propagation of APs into dendrites. Experiments were performed to test the hypothesis that Kv4.2 channels are differentially trafficked at different regions along the apical dendrite during basal activity and upon stimulation in CA1 neurons. Proximal (50-150 μm from the soma, primary and oblique) and distal (>200 μm) apical dendrites were selected. The fluorescence recovery after photobleaching (FRAP) technique was used to measure basal cycling rates of EGFP-tagged Kv4.2 (Kv4.2g). We found that the cycling rate of Kv4.2 channels was one order of magnitude slower at both primary and oblique dendrites between 50 and 150 μm from the soma. Kv4.2 channel cycling increased significantly at 200 to 250 μm from the soma. Expression of a Kv4.2 mutant lacking a phosphorylation site for protein kinase-A (Kv4.2gS552A) abolished this distance-dependent change in channel cycling; demonstrating that phosphorylation by PKA underlies the increased mobility in distal dendrites. Neuronal stimulation by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) treatment increased cycling of Kv4.2 channels significantly at distal sites only. This activity-dependent increase in Kv4.2 cycling at distal dendrites was blocked by expression of Kv4.2gS552A. These results indicate that distance-dependent Kv4.2 mobility is regulated by activity-dependent phosphorylation of Kv4.2 by PKA.
    Hippocampus 05/2012; 22(5):969-80. DOI:10.1002/hipo.20899 · 4.16 Impact Factor
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    • "A role for AKAP proteins in regulating AMPAR-mediated currents, AMPAR trafficking, and synaptic plasticity has been well established (Snyder et al., 2005; Smith et al., 2006; Lu et al., 2007; Nie et al., 2007; Tunquist et al., 2008; Bhattacharyya et al., 2009; Weisenhaus et al., 2010). The induction and expression of synaptic plasticity is accompanied by changes neuronal excitability (intrinsic plasticity) (Bliss and Lomo, 1973; Watanabe et al., 2002; Frick et al., 2004; Xu et al., 2005; Disterhoft and Oh, 2006; Narayanan and Johnston, 2007; Campanac et al., 2008; Jung and Hoffman, 2009; Rosenkranz et al., 2009) and recent studies have found that ion channel modulation and trafficking contribute to plasticity-induced alterations in neuronal function (Zhang and Linden, 2003; Shah et al., 2010). Intrinsic plasticity has been hypothesized to act as an additional memory-storage mechanism (Zhang and Linden, 2003). "
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    ABSTRACT: Kv4.2, as the primary α-subunit of rapidly inactivating, A-type voltage-gated K(+) (Kv) channels expressed in hippocampal CA1 pyramidal dendrites, plays a critical role in regulating their excitability. Activity-dependent trafficking of Kv4.2 relies on C-terminal protein kinase A (PKA) phosphorylation. A-kinase-anchoring proteins (AKAPs) target PKA to glutamate receptor and ion channel complexes to allow for discrete, local signaling. As part of a previous study, we showed that AKAP79/150 interacts with Kv4.2 complexes and that the two proteins colocalize in hippocampal neurons. However, the nature and functional consequence of their interaction has not been previously explored. Here, we report that the C-terminal domain of Kv4.2 interacts with an internal region of AKAP79/150 that overlaps with its MAGUK (membrane-associated guanylate kinase)-binding domain. We show that AKAP79/150-anchored PKA activity controls Kv4.2 surface expression in heterologous cells and hippocampal neurons. Consistent with these findings, disrupting PKA anchoring led to a decrease in neuronal excitability, while preventing dephosphorylation by the phosphatase calcineurin resulted in increased excitability. These results demonstrate that AKAP79/150 provides a platform for dynamic PKA regulation of Kv4.2 expression, fundamentally impacting CA1 excitability.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2011; 31(4):1323-32. DOI:10.1523/JNEUROSCI.5383-10.2011 · 6.34 Impact Factor
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