Modelling the role of βCaMKII in regulating bidirectional plasticity at parallel fibre–Purkinje cell synapses
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1
University of Hertfordshire, Science and Technology Research Institute, United Kingdom
Synaptic plasticity, the strengthening and weakening of connections between neurons, is crucial for learning and memory in neuronal circuits. However, a better comprehension of the mechanisms of many forms of synaptic plasticity is limited by the complexity of the underlying intracellular signalling pathways.
Cerebellar long-term depression (LTD) and potentiation (LTP) are calcium-dependent forms of synaptic plasticity that weaken and strengthen synapses between parallel fibres (PF) and Purkinje cells (PCs). While LTD is induced by large increases in intracellular calcium concentrations in response to paired PF and climbing fibre (CF) input, smaller calcium concentration increases that result from PF input alone lead to LTP. The induction of LTD and LTP is mediated by enzymes such as calcium/calmodulin-dependent kinase type II (CaMKII) and protein phosphatase 2B (PP2B) that regulate the phosphorylation and dephosphorylation of postsynaptic AMPA receptors.
The CaMKII holoenzyme is composed of αCaMKII and βCaMKII isoforms. Recent experiments with Camk2b knockout mice have revealed that βCaMKII, which is the predominant CaMKII isoform in the cerebellum, controls the direction of plasticity at the PF–PC synapse (van Woerden et al., 2009). More specifically, protocols that induce LTD in wild-type mice result in LTP in knockout mice that lack βCaMKII, and vice versa.
Here, we use a simple model of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and PP2B to investigate the mechanisms that underlie the regulation of bidirectional plasticity at the PF–PC synapse. The model is based on our recent model of CaMKII activation (Pinto et al., 2012). In the model, the binding of calcium to calmodulin (CaM), the activation of CaMKII and PP2B by calcium/calmodulin (Ca4–CaM), and the AMPA receptor phosphorylation and dephosphorylation are represented by coupled ordinary differential equations.
Van Woerden et al. (2009) suggested that the sign reversal of synaptic plasticity in the Camk2b knockout mice is due to a biochemical difference between the α and βCaMKII isoforms. The βCaMKII, but not αCaMKII, subunits can bind to filamentous actin (F-actin), which could result in clustering of the CaMKII holoenzyme to F-actin, making it unavailable for AMPA receptor phosphorylation. We included the binding of CaMKII to F-actin in our simulations of synaptic plasticity induction in wild-type mice, whilst omitting it when modelling plasticity induction in Camk2b knockout mice. Moreover, Purkinje cells contain about four times as much βCaMKII as αCaMKII, and the loss of βCaMKII did not result in up-regulation of αCaMKII in the knockout mice. Thus, we also included the corresponding reduction in CaMKII concentration in our simulations of knockout mice.
We simulate the induction of synaptic plasticity in response to PF stimulation with and without paired CF stimulation in our model by applying calcium pulses with concentrations that reflect experimental data, and we record the resulting phosphorylation and dephosphorylation of AMPA receptors. Our simulations replicate the experimental findings by van Woerden et al. (2009), suggesting that the binding of βCaMKII to F-actin can indeed contribute to the control of bidirectional plasticity at PF–PC synapses. Our model predicts that the sign reversal of synaptic plasticity is based on a combination of three mechanisms operating at different calcium concentrations. At the low calcium concentrations that result from PF input alone, the loss of F-actin binding in the knockout mice leads to increased availability of active CaMKII compared to the wild-type mice, and to induction of LTD rather than LTP. At the high calcium concentrations that are triggered by paired PF and CF input, the reduced CaMKII concentration in the knockout mice favours the dephosphorylation of AMPA receptors by PP2B, and the induction of LTP instead of LTD. This effect is exacerbated by the increased availability of Ca4–CaM that results from the decreased CaMKII levels, which further increases the activation of PP2B.
References
Van Woerden, G.M., Hoebeek, F.E., Gao, Z., Nagaraja, R.Y., Hoogenraad, C.C., Kushner, S.A., Hansel, C., De Zeeuw, C.I., Elgersma, Y.: [beta]CaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses. Nature Neuroscience 12, 823–825 (2009).
Pinto, T.M., Schilstra, M.J., Steuber, V.: The Effective Calcium/Calmodulin Concentration Determines the Sensitivity of CaMKII to the Frequency of Calcium Oscillations. Lecture Notes in Computer Science 7223, 131-135 (2012).
Keywords:
Calcium,
Calmodulin,
Cerebellum,
Learning,
Long-term depression,
Long-Term Potentiation,
Memory,
simulation
Conference:
Bernstein Conference 2012, Munich, Germany, 12 Sep - 14 Sep, 2012.
Presentation Type:
Poster
Topic:
Learning, plasticity, memory
Citation:
Pinto
TM,
Schilstra
MJ and
Steuber
V
(2012). Modelling the role of βCaMKII in regulating bidirectional plasticity at parallel fibre–Purkinje cell synapses.
Front. Comput. Neurosci.
Conference Abstract:
Bernstein Conference 2012.
doi: 10.3389/conf.fncom.2012.55.00188
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Received:
11 May 2012;
Published Online:
12 Sep 2012.
*
Correspondence:
Mr. Thiago M Pinto, University of Hertfordshire, Science and Technology Research Institute, Hatfield, Herts, AL10 9AB, United Kingdom, t.pinto@herts.ac.uk