Experience-dependent plasticity is the adaptability of brain circuits as a result of changes in neural activity, a phenomenon that has been proposed as the neural basis for important brain function in health and disease. The underlying mechanisms of experience-dependent plasticity can take different forms, depending on the organisms and brain areas under investigation. A better understanding of these mechanisms will help to interpret normal brain function as well as to guide therapies for neurological diseases. Mouse vibrissa system offers great experimental advantages to studying experience-dependent plasticity and the underlying molecular mechanisms at different levels. Using sensory experience paradigms of unbalanced whisker activity, we find that sensory experience induces rapid synaptic strengthening at excitatory synapses converged onto single layer 2/3 pyramidal neurons, although the plasticity at these synapses displays remarkable input specificity. Furthermore, we discover that recently potentiated layer 4-2/3 excitatory synapses are labile and subject to activity-dependent weakening in vitro. Calcium-permeable AMPARs (CP-AMPARs) that are sometimes associated with synaptic strengthening are not essential for activity-induced synaptic weakening. Finally, we demonstrate that ongoing sensory experience triggers distinct phases of synaptic plasticity, which are tightly correlated with changes in NMDAR properties and function. Taken together, the results from this thesis show distinct manifestations and mechanisms of how sensory experience modulates synaptic properties and neuronal function that may provide insights into information processing and coding in the neocortex.

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Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

The mammalian neocortex comprises a diverse population of excitatory neurons that perform distinct roles in the neocortical circuit. These neurons are born from a heterogeneous population of progenitor cells during embryonic development and it is increasingly being recognised that individual progenitors can impart specific functional characteristics to their offspring. For example, clonally-related sister neurons in mouse neocortex are biased to form gap junctions with one another early in development, to form synaptic connections with one another as they mature, and to show similar response properties in the adult. This highlights a fundamental role for neuronal lineage in the formation of precise neocortical connectivity. However, the extent to which neuronal phenotype is determined by lineage, and the process by which this arises, is not fully understood. Nor is it known whether similar lineage relationships exist in the human neocortex. Deciphering neocortical lineage relationships has been limited by the techniques available to identify and manipulate clonally-related neurons. In this thesis I have developed novel molecular tools for the identification and manipulation of clonally-related neurons and refined their use by in utero surgery in mice. I first developed a retrovirus encoding Cre recombinase and demonstrated that this can be successfully combined with reporter mice to capitalise on optogenetics for functional studies. In an effort to establish a reliable and unequivocal method of identifying clonally-related neurons, I then constructed a retrovirus encoding genetically-distinct RNA barcodes. I confirmed that the RNA barcode could be reliably retrieved from single neurons and used to determine clonal relationships in mouse neocortex and in an in vitro model of human neocortex derived from induced pluripotent stem cells (iPSCs). By comparing the dendritic morphology of barcoded mouse neocortical neurons, I was able to demonstrate that the dendritic arbor of clonally-related neurons is more similar than control neurons derived from different progenitors. This may contribute to specific patterns of synaptic connectivity amongst clonally-related neurons. Within the iPSC system, I demonstrate the utility of the retroviral RNA barcode and revealed that clonally-related human neocortical cells exhibit a higher probability of being gap-junction coupled. These studies advance our understanding of lineage relationships in neocortical excitatory neurons in mouse and provide the first evidence that human neocortical clones exhibit similar functional relationships to those observed in the rodent neocortex.

Stimulation of dopamine D2S receptor introduced in Balb/c-3T3 cells induces Galphai3-dependent transformation. Galphai3 interacts with DED2-containing protein, TNFAIP8, in yeast mating and in FLAG-TNFAIP8 transfected Balb/c-3T3 cells. TNFAIP8 inhibits caspase-8 activity and is elevated in certain cancers as well as in metastatic, radiation resistant, chemo-resistant and angiogenic tumours. This study looks at Galphai3 activation of TNFAIP8 leading to the inhibition of TNFalpha-induced cell death in Balb/c-3T3 cells coexpressing D2S and either TNFAIP8 over-expression or TNFAIP8 antisense-knockdown with assays for foci formation, cell death and executioner caspase activation. The data showed D2S increases basal foci formation; this is blocked in TNFAIP8 antisense cells. D2S activation further increases foci formation; also completely blocked in TNFAIP8 antisense cells. D2S activation reduces cell death except in TNFAIP8 antisense cells. D2S activation reduces caspase-active cells. These results show that D2S mediated inhibition of caspase activity and death resulting in transformation is dependent on TNFAIP8.

This thesis explores thyroid hormone (TH) effects on adult neuroendocrine brain and pituitary in goldfish (Carassius auratus) to address the hypothesis that THs regulate the reproductive neuroendocrine axis through effects on gamma-aminobutyric acid (GABA), a neurotransmitter that stimulates gonadotropin release in fish. The experimental approach was to increase circulating levels of the TH 3,5,3'-triiodothyronine (T3) in goldfish through waterborne exposures, and measure effects on gene expression, enzyme activity and hormone levels in comparison to controls. In sexually regressed males, T3 exposure decreased gene expression of GABA-synthetic and degradative enzymes (glutamic acid decarboxylase and GABA-transaminase, respectively) in telencephalon in a time- and dose-dependent manner but not in hypothalamus. GABA-transaminase activity was not affected by this T3 challenge. In sexually mature males and females, T3 treatment resulted in increased follicle stimulating hormone beta subunit expression in pituitary in females only, and had no effect on luteinizing hormone (LH) beta subunit expression or circulating LH levels in eider sex. Further experiments with GABA agonists indicated that T3 exposure had no effect on GABA-mediated LH release. TH receptor expression was affected in a tissue-specific manner by T3 exposure, appearing to be autoregulated in pituitary, but unaffected in neuroendocrine brain regions. TH deiodinase expression in brain and pituitary and thyroid stimulating hormone beta subunit expression in pituitary was affected in a manner reflective of negative feedback by T3 to reduce T3 levels in tissues and in circulation to a set-point. Gene expression profiling with cDNA microarrays indicated a large-scale decrease in gene expression in adult male goldfish telencephalon in response to T3. This included genes encoding proteins with functions central to general metabolic activity including mRNA splicing and proteasomal protein turnover, as well as neuroendocrine signalling relevant to reproduction and neurogenesis. In conclusion, THs have the potential to regulate the reproductive neuroendocrine axis through minor effects on GABA function in neuroendocrine brain and sex-dependent effects on glycoprotein hormone subunit gene expression, except for LH beta, in pituitary. Moreover, gene expression in adult teleost brain is responsive to TH, which is critical to understanding the potential for TH regulation of the reproductive neuroendocrine axis in teleosts.

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