Compared to mammals, nematodes appear to exhibit a unique GABAergic nervous system. Haemonchus controtus is a parasitic nematode that infects ruminants worldwide. Hco-UNC-49 is a H. contortus GABA-gated chloride channel and is an orthologue to the UNC-49 channel from the free-living nematode Caenorhabditis elegans. Previous research by our group has shown that while the UNC-49 channels from the two nematodes share similar sequence homology they do not share identical sensitivity to GABA. To further investigate the characteristics of the Hco-UNC-49 channel, this study tested the effects of various modulators, insecticides and anti-parasitic drugs on channel function. Most notably, the molecules penicillin G, propofol and pregnenolone sulfate all had similar effects on Hco-UNC-49 as reported previously for Cel-UNC-49. On the other hand, Hco-UNC-49 appears to be less sensitive to picrotoxin inhibition compared to what has been reported for Cel-UNC-49. Novel effects of a number of anthelmintics were also observed. For example, the anthelmintics ivermectin and moxidectin both enhanced Hco-UNC-49 GABA responses, while piperazine was able to directly activate Hco-UNC-49 at high concentrations. These results suggest that Hco-UNC-49 is likely an in vivo target for these anthelmintics. / UOIT

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a genetic component. Most candidate gene association studies have given mixed results. We investigated the GABAA receptor gamma2 subunit gene GABRG2, the dopamine receptor gene DRD3, and the Brain-derived neurotrophic factor gene BDNF that is required for D3 expression by genotyping polymorphisms spanning and surrounding these genes for association with SCZ, as well as suicidal behaviour. We also examined the BDNF, DRD3, as well as the dopamine receptor gene DRD2 and Protein Kinase B gene AKT1 for association with Tardive Dyskinesia (TD), a potentially irreversible motor side effect of long-term antipsychotic medication. Our analysis included single-marker tests, haplotype tests, and gene-gene interactions. We found a haplotype in the 5’ region of GABRG2 to be associated with SCZ in both families and matched case-control samples. We also found two synonymous DRD2 polymorphisms, rs6275 (C939T) and rs6277 (C957T), and their haplotypes, as well as a polymorphism 5’ of DRD3, rs905568, to be associated with TD. Further, we reviewed two putative functional DRD2 polymorphisms, -141C Ins/Del and TaqIA, in TD and found TaqIA 3’ of the gene to be associated with TD in a meta-analysis. Lastly, we found a significant interaction between AKT1 rs3730358 and DRD2 C939T in TD. Though replication studies are required, these results contribute to the future development of genetic tests to assess for the risks of SCZ and TD, leading to better outcome for patients suffering from these debilitating conditions.

Brain development and function depend on intrinsic and extrinsic factors. In particular, the proper functioning of sensory systems can be altered according to the quality of extrinsic sensory information received during life. In this context, questions concerning neuroplasticity take on special relevance when considering that sensory experience has a big impact on the degree of plasticity of the brain. In this thesis, we have sought to understand how visual deprivation affects the development and maintenance of visual centers in the brain and the role of visual deprivation on plasticity throughout life. We have addressed this question by studying the retinocollicular projection, which is the neuronal pathway that connects the retina with a visual input processing center, the superior colliculus (SC). Unexpectedly, we found that in Syrian hamsters (Mesocricetus auratus) the size of receptive fields (RFs) of neurons in the SC is plastic in adult animals if they have been deprived of a minimum of visual experience when juveniles. Specifically, dark-reared (DR) hamsters refine SC RFs as do their normally-reared counterparts, but they lose RF refinement if they remain in the dark after their RFs get refined. We found that a well defined period and duration of visual experience can stabilize RF size in adulthood. Furthermore, we sought to investigate the mechanisms by which RF size is increased in adult DR hamsters. By testing the strength of intracollicular inhibition using electrophysiological and molecular techniques, we have found that visually-deprived animals have weaker inhibitory circuitry in their SC than normal animals. The quantity of GABA receptors and GABA containing neurons is decreased in the SC of adult DR animals. We propose that these results explain at least in part the RF enlargement we find in visually-deprived animals. Knowledge from this study provides general insight into sensory system plasticity in adulthood and new information about visual system development that is relevant for treatments of diseases.

It is well established that the septo-hippocampal system is involved in memory. The medial septum is connected to the hippocampus via the fimbria fornix, which consists mostly of acetylcholine and ã-aminobutyric acid (GABA) projection neurons. The contributions of the cholinergic projection to memory have been studied extensively; whereas, the role of the GABAergic projection is not well characterized. The present experiment tested whether septal infusions of the selective H-channel blocker ZD7288 would impair spontaneous alternation (SA) and continuous multiple inhibitory avoidance (CMIA). Fifteen minutes prior to assessing SA or CMIA, different groups of male Sprague-Dawley rats were given septal infusions of saline or ZD7288 (0.2, 0.6 or 1.5 nmol / 0.5ìl). Our results indicate that septal infusions of ZD7288 impaired SA in a dose-dependent manner; the same infusions did not affect CMIA. This is the first demonstration that H-channels on septo-hippocampal GABAergic projection neurons are involved in memory.

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a genetic component. Most candidate gene association studies have given mixed results. We investigated the GABAA receptor gamma2 subunit gene GABRG2, the dopamine receptor gene DRD3, and the Brain-derived neurotrophic factor gene BDNF that is required for D3 expression by genotyping polymorphisms spanning and surrounding these genes for association with SCZ, as well as suicidal behaviour. We also examined the BDNF, DRD3, as well as the dopamine receptor gene DRD2 and Protein Kinase B gene AKT1 for association with Tardive Dyskinesia (TD), a potentially irreversible motor side effect of long-term antipsychotic medication. Our analysis included single-marker tests, haplotype tests, and gene-gene interactions. We found a haplotype in the 5’ region of GABRG2 to be associated with SCZ in both families and matched case-control samples. We also found two synonymous DRD2 polymorphisms, rs6275 (C939T) and rs6277 (C957T), and their haplotypes, as well as a polymorphism 5’ of DRD3, rs905568, to be associated with TD. Further, we reviewed two putative functional DRD2 polymorphisms, -141C Ins/Del and TaqIA, in TD and found TaqIA 3’ of the gene to be associated with TD in a meta-analysis. Lastly, we found a significant interaction between AKT1 rs3730358 and DRD2 C939T in TD. Though replication studies are required, these results contribute to the future development of genetic tests to assess for the risks of SCZ and TD, leading to better outcome for patients suffering from these debilitating conditions.

Cocaine (CA) exposure during pregnancy causes long-lasting negative effects on fetal brain development and eventually results in motor dysfunction or changes in learning and memory performance. £^-amino-butyric acid (GABA) is the primary inhibitory neurotransmitter in the adult brain and undergo a switch from excitatory to inhibitory during early postnatal period. The excitatory/inhibitory switch is resulted in the relative temporal expression of K+-Cl- cotransporter 2 (KCC2). GABA is the neurotransmitter in the rat was born from excitement to inhibition and until the growth of thirty days have completely inhibitory. Here we test the effect of CA prenatal exposure on the expression of KCC2 in prefrontal cortex (recognition), hippocampus (memory), VTA (reward) and nucleus accumbens (reward). Protein expression profile of control or prenatal CA treated groups were evaluated by western blot in 2 days interval from postnatal day (PND) 8 to 30. The expression of KCC2 was time-dependently enhanced from PND 8 and reaches its maximal expression around PND 18 in prenatal CA exposure groups. The time-dependent profile of KCC2 expression in prefrontal cortex and NAc was significantly delayed in prenatal CA exposure group. We then correlate the KCC2 expression and the cocaine sensitivity by locomotor activity assay. We found group A shows a higher sensitivity to cocaine than group B in control rats. Surprisingly, group A of prenatal cocaine reduce the sensitive to cocaine to a similar extend like group B in control rats, suggesting prenatal exposure of cocaine might enhance the KCC2 expression. Furthermore, age range of A group (PND 22~27) and B group (PND 29~34) to repeated cocaine exposure resulted in up-regulation of KCC2 expression in B group earlier than A group. We found that the KCC2 expressions of repeated cocaine exposure in B group were higher than A group. In other words, in the B group, the inhibitory effect of GABA was significant and the locomotor activity was relatively slow. Therefore, the A group was more easy be cocaine addiction than B group. We next explore the signaling mechanism underlying cocaine exposure-induced KCC2 expression inhibition. Brain slices were incubated with cocaine with or without dopamine receptor antagonists and KCC2 expression was evaluated by western blot. Either SCH23390 (dopamine D1-receptor inhibitor) or eticlopride (dopamine D2-receptor inhibitor) significantly hamper the inhibition of KCC2 expression by cocaine in normal slices. However, only D2 antagonist eticlopride but not SCH23390 is effective reverse cocaine-induced KCC2 expression inhibition. Overall, results from our current studies provide a further insight into the molecular mechanism of cocaine-induced synaptic modification.

Thesis (Ph. D.)--Case Western Reserve University, 2004. / [School of Medicine] Department of Neurosciences. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thèse (M.Sc.)--Université Laval, 2008. / Bibliogr.: f. [69]-77. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Thesis (Ph. D.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains xii, 231 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy