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Plasticity supports the remarkable adaptability and robustness of cortical processing. It allows the brain to learn and remember patterns in the sensory world, to refine motor control, to predict and obtain reward, or to recover function after injury. Behind this great flexibility hide a range of plasticity mechanisms, affecting different aspects of neuronal communication. However, little is known about the precise computational roles of some of these mechanisms. Here, we show that the interaction between spike-timing dependent plasticity (STDP), intrinsic plasticity and synaptic scaling enables neurons to learn efficient representations of their inputs. In the context of reward-dependent learning, the same mechanisms allow a neural network to solve a working memory task. Moreover, although we make no any apriori assumptions on the encoding used for representing inputs, the network activity resembles that of brain regions known to be associated with working memory, suggesting that reward-dependent learning may be a central force in working memory development. Lastly, we investigated some of the clinical implications of synaptic scaling and showed that, paradoxically, there are situations in which the very mechanisms that normally are required to preserve the balance of the system, may act as a destabilizing factor and lead to seizures. Our model offers a novel explanation for the increased incidence of seizures following chronic inflammation.
Synaptopodin is the founding member of a family of actin-associated proline-rich proteins. It is present in a subset of telencephalic dendritic spines, where it is tightly associated with the dendritic spine apparatus, a putative calcium store. Synaptopodin-deficient mice lack the spine apparatus and show deficits in long-term potentiation and spatial memory. Thus, synaptopodin appears to play a role in synaptic plasticity. In the present thesis, three major questions were addressed: (1) What is the distribution of synaptopodin and the spine apparatus in identified hippocampal neurons? (2) Is the distribution of synaptopodin affected by denervation? (3) Is synaptopodin involved in the regulation of denervation-induced spine loss? The major findings of this thesis are: (1) Immunohistochemistry in the hippocampus of wildtype and EGFP-transgenic mice revealed significant layer-specific differences in the prevalence of synaptopodin at the level of individual neurons. (2) Light and electron microscopic analysis also revealed the presence of synaptopodin in axon initial segments of cortical and hippocampal principal neurons. There, it was found to be an essential component of the cisternal organelle, a putative axonal homologue of the dendritic spine apparatus. (3) Immunohistochemistry in the rat fascia dentata before and following entorhinal deafferentation revealed changes in synaptopodin expression in denervated and non-denervated layers of the hippocampus, suggesting that the distribution of synaptopodin in hippocampal neurons is regulated by presynaptic signals. (4) The dynamics of denervation-induced spine plasticity were studied in vitro using confocal live imaging of organotypic entorhino-hippocampal slice cultures. Whereas spines were remarkably stable under control conditions, spine loss and spine formation were seen following denervation. No significant differences were observed between cultures from wildtype and synaptopodin-deficient mice, suggesting that synaptopodin is not involved in lesion-induced spine plasticity. (5) Finally, a set of transgenic mice expressing fluorescently tagged synaptopodin were generated to facilitate future experiments on the dynamics and function of synaptopodin. In summary, this thesis presents novel findings on (1) the subcellular distribution of synaptopodin in spines and the axon initial segment, (2) the molecular composition of the cisternal organelle, and (3) the dynamics of spines and the spine apparatus organelle following deafferentation in vivo and in vitro.