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Human brain evolution granted us cognitive and behavioral capabilities that are unique amongst animals. SRGAP2 is a gene that was specifically duplicated in the human lineage and plays roles in the regulation of cortical development and synapse dynamics. As paralogs of one of the few known genes that regulates excitatory and inhibitory synapses concurrently, the duplications of SRGAP2 were well-positioned during human evolution to gain novel functions leading to the cognitive and behavioral phenotypes exhibited in humans. SRGAP2C, a human-specific paralog of the ancestral SRGAP2 gene, inhibits every known function of SRGAP2 and induces a phenotype similar to SRGAP2 knockdown. This induces neoteny in the maturation of synapses in mice, allowing us to study a putatively “human-like” phenotype in the mouse brain. While studies have been conducted on the effects of SRGAP2 manipulation in juvenile and young adult mice, its effects on older mice has yet to be determined. In this dissertation, we perform longitudinal imaging experiments to determine the effects of SRGAP2 manipulation in the cortex of adult mice. In Chapter 3, we first examine the effects of SRGAP2 knockdown on the spine dynamics on apical dendrites of layer 5 pyramidal cells in the barrel cortex of adult mice, determining how it regulates spine density, turnover, and survival at baseline and in response to sensory deprivation. In Chapter 4, we study how SRGAP2 knockdown affects the clustered formations of new dendritic spines on the apical dendrites of layer 5 pyramidal cells in the barrel cortex of adult mice. Together, these results represent the first demonstration of SRGAP2 regulating on synapse dynamics in vivo and show that SRGAP2 knockdown can be used to model human brain evolution in adult mice.

published_or_final_version / Biochemistry / Master / Master of Philosophy

The formation of patterns of functionally appropriate chemical synapses is one of the key aspects of nervous system development. I have investigated the cellular interactions that culminate in the formation of an inhibitory synapse between the R and P neurons of the leech. These neurons may be isolated and maintained in culture, where they reform synaptic connections under easily manipulable conditions. An early event in the formation of this synapse is the loss from sites of contact in the postsynaptic P cell of an excitatory response to the transmitter serotonin. The loss of this response was triggered specifically by contact with the presynaptic R neuron, and not by contact with other leech neurons, including other serotonergic neurons. Furthermore, contact with the R neurons of the reproductive ganglia, which do not innervate P cells, was also ineffective in causing the loss of response. This highly specific cellular interaction was prevented by treatment of the R cell surface with the proteolytic enzyme trypsin or with the lectin wheat germ agglutinin (WGA), suggesting involvement of an R cell surface glycoprotein. WGA blocked not only the loss of the excitatory response, but also prevented the formation of the R-P synapse. An antibody library against the R cell generated using a novel phage-display system produced antibodies which bound to subsets of leech neurons, including the R neurons, but none of these was specific for the R cells. I conclude that an early event in the formation of the R-P synapse is the recognition by the P cell of its correct synaptic partner through an R cell-specific surface molecule.

I explored the relationship between neurite outgrowth and the onset of synaptic activity in the central neuropil of the leech embryo. In order to follow changes in early morphology and the onset of synaptic activity in the same identified neuron, whole cell patch clamp recordings and fluorescent dye fills were obtained from dorsal pressure-sensitive (P) cells, the first neurons that could be reliably identified in the early embryo. I followed the development of the P cell from the first extension of neurites to the elaboration of an adult-like arbour. Following the growth of primary neurites, we observed a profuse outgrowth of transient neurites within the neuropil that retracted to form spurs. Following a dormant period, stable secondary branches grew from the spurs and became tipped with terminals. At this time, neurites of the Retzius (R) cell, a known presynaptic partner in the adult, were observed to contact the terminals. Although voltage-dependent currents were seen in the P cell at the earliest stage, spontaneous synaptic activity was only observed when terminals had formed. Spontaneous release was observed before evoked release could be detected from the R cell. The results suggest that transient neurites are formed during an exploratory phase of development, whereas the more precisely timed outgrowth of stable neurites from the spurs signals functional differentiation during synaptogenesis. As spurs have also been observed in neurons of the mammalian brain, they may constitute a primordial synaptic organizer.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Thesis supervisor: Joshua A. Weiner. Includes bibliographic references (p. 105-121).

Thesis (Ph. D.)--University of Oregon, 2005. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 76 - 80). Also available for download via the World Wide Web; free to University of Oregon users.

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