Regulation of neuronal morphology and synaptic development by activity

In this dissertation, I review current knowledge on activity-dependent neural development, focusing on neuronal morphogenesis and synapse development. I also present original research on the activity-dependence of two specific aspects of development: GABAergic synapse establishment and dendrite growth.; Neural activity is known to regulate the number and properties of GABAergic synapses in the brain, but the mechanisms underlying these changes are unclear. We find that blocking spike activity globally in developing hippocampal cultures caused a dramatic reduction in the density of GABAergic terminals, as visualized by immunocytochemistry, as well as a reduction in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). In contrast to blockade of network activity, hyperpolarizing or abolishing spike activity in single neurons altered neither the density of incoming inhibitory synaptic terminals nor the properties of mIPSCs. Suppressing activity in individual presynaptic GABAergic neurons also failed to decrease the number of output synaptic terminals. Our results indicate that GABAergic synapses made on a postsynaptic neuron are regulated by the level of activity in surrounding neurons.; Voltage-gated sodium channels underlie electrical excitability of most neurons. We report an unexpected role for these channels in dendritic development. Loss of channel expression in single hippocampal neurons in culture reduces the number of primary dendrites arising from the soma and the total length of each dendrite. The two phenotypes could be dissociated. The reduction in the number of primary dendrites is due to loss of the protein itself, and occurs in the early stages of morphological development. In contrast, the reduction in length of each primary dendrite occurs later in development and could be reversed by suppressing activity in the entire network of neurons. Therefore, the initial specification of primary dendrites is controlled by activity-independent, intrinsic factors and the subsequent growth of dendrites is regulated by electrical activity relative to neighboring neurons.