This research project will use a detailed, complex compartmental model of a cerebellar Purkinje cell to explore how changes in Ca2+ concentration ([Ca2+]), caused by inflow through Ca2+ channels and by release from internal stores, can affect dendritic excitability and synaptic plasticity in a large neuron. The Purkinje cell has been used as an experimental model for the investigation of metabotropic receptors, Ca2+ release from cytoplasmic stores evoked by Ca2+ and inositol triphosphate, and synaptic plasticity. At present, the functional role of these mechanisms is unclear and their interactions are poorly understood. By simulating a detailed, realistic model which integrates all these processes, we expect to make predictions on how such [Ca2+]- regulating mechanisms can interact with synaptic inputs in vivo. This research will not only contribute to our understanding of how the Purkinje cell functions within the cerebellar network, but will also provide insights in general mechanisms that control neural firing properties and learning in cortex and hippocampus. We will expand an existing detailed compartmental model of the Purkinje cell to include Ca2+ diffusion, buffering, pumps and uptake and release by internal stores in all dendritic compartments. The model will be tuned to reproduce high-resolution fura-2 Ca2+ imaging data, obtained in another laboratory. Subsequently, we will also include simple models of metabotropic receptor-activated Ca2+ release from internal stores and [Ca2+]-controlled synaptic plasticity of granule cell and inhibitory inputs. We will simulate changes in [Ca2+] evoked by diverse synaptic inputs. These simulations will be used to predict spatial and temporal changes in [Ca2+] under conditions of synaptic inputs in vivo, and to examine the interactions between the climbing fiber and parallel fiber systems at the level of [Ca2+]. We will examine the effects of [Ca2+] on the variability of amplification by Ca2+ currents of granule cell synaptic inputs. Subsequently, we will use the model to examine how metabotropic receptor activated Ca2+ release from internal stores could modulate synaptic integration by Purkinje cells. We expect that activation of metabotropic receptors might have a pronounced effect on dendritic excitability. We will also use the model to investigate the possible role of the Na+/Ca2+ exchanger in the prolonged depolarizations observed after pharmacological activation of the metabotropic receptor. Finally, we will use the model to examine which [Ca2+] profiles are necessary to induce long term depression (LTD) and other forms of synaptic plasticity. From these results, a simple model of synaptic plasticity will be built and used to explore which combinations and temporal patterns of climbing fiber and parallel fiber inputs could be expected to cause synaptic plasticity.
| De Schutter, E (1999) Using realistic models to study synaptic integration in cerebellar Purkinje cells. Rev Neurosci 10:233-45 |
| De Schutter, E (1998) Dendritic voltage and calcium-gated channels amplify the variability of postsynaptic responses in a Purkinje cell model. J Neurophysiol 80:504-19 |
| De Schutter, E (1997) A new functional role for cerebellar long-term depression. Prog Brain Res 114:529-42 |
| De Schutter, E; Maex, R (1996) The cerebellum: cortical processing and theory. Curr Opin Neurobiol 6:759-64 |
