Synaptic mechanisms of Hebbian and homeostatic plasticity driven by intrinsic activity in the developing hippocampus
Year: 2013
Type: dissertation
Abstract: The formation of synaptic connections in the brain is guided by genetic and activity-dependent mechanisms. The initial hard-wiring of the circuitry is followed by a phase during which connections are refined. During this process the genetic factors are less important and refinement is guided by electrical activity. However, the mechanisms underlying the activity-driven synaptic fine-tuning are still poorly understood. The features of electrical activity and the mechanisms of synaptic transmission differ in the developing networks as compared to those of the adult. Electrical activity in the developing networks comprises of intermittent, highly synchronous bursts of action potentials interleaved by more silent, asynchronous neuronal firing. In the hippocampus this immature-type electrical patternity coincides temporally with the intense synaptic reorganization. Moreover, there is a parallel, developmentally-regulated expression GluA4 subunit of AMPA-type ionotropic glutamate receptors in the hippocampal neurons. Despite frequent speculation on the relative importance of synchronous vs. asynchronous neuronal activity on the synaptic development in the brain, there have been no direct experiments to study this issue. In this thesis we have, for the first time, been able to experimentally dissect the roles of asynchronous vs. synchronous activity on synaptic refinement in the hippocampus. Specifically, we show that spontaneous synchronous activity is essential for the stabilization and maturation of immature CA3-CA1 synapses, and that network desynchronization leads to weakening of glutametergic transmission in the CA1 area. Plasticity changes caused by different endogenous activity patterns were strongly dependent on the synapse type (glutamatergic vs. GABAergic), the anatomical area (CA1 vs. CA3) and maturational stage of the neurons. In addition, the GluA4 was shown to be critical for both the Hebbian type and homeostatic plasticity mechanisms in developing glutamatergic synapses. In the absence of GluA4, the homeostatic regulation of the immature glutamatergic networks in response to manipulation of endogenous activity patterns was perturbed. Finally, GluA4 was shown to be necessary and sufficient for protein kinase A dependent long-term potentiation (LTP), typical of immature CA3-CA1 synapses. These data demonstrate the instrumental role of spontaneous synchronous activity and GluA4 AMPAR subunit expression in the formation and refinement of hippocampal synaptic networks.
Source: Työväentutkimus Vuosikirja
Author: Johanna Huupponen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1944591947