Molecular and Cellular Neuroscience Commons^™

Phosphorylation Of Tau Protein At Thr175 Is A Toxic Event Associated With Neurodegeneration, Alexander Moszczynski

Electronic Thesis and Dissertation Repository

Aberrant phosphorylation and pathological deposition of the microtubule associated protein tau (tau protein) is associated with toxicity and cellular death in a number of neurodegenerative diseases (tauopathies). Specific phosphorylation sites are of interest in the processes leading to tau protein toxicity. One site of interest on tau protein is Thr¹⁷⁵ (pThr¹⁷⁵), which has been identified in diseased brain tissue from individuals with amyotrophic lateral sclerosis with cognitive impairment (ALSci) and Alzheimer’s disease. In vitro, pseudophosphorylation at this residue has been shown to induce the formation of pathological tau fibrils and, apoptotic cell death.

In my thesis, …

Amelioration Of Prenatal Alcohol Effects By Environmental Enrichment In A Mouse Model Of Fasd, Aniruddho Chokroborty-Hoque

Electronic Thesis and Dissertation Repository

Maternal alcohol consumption during pregnancy results in a spectrum of behavioural and cognitive deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). Currently, little is know about if and how the external environment may modulate these deficits. I have used C57BL/6 mice to study this interaction between prenatal alcohol exposure and the postnatal environment. Alcohol exposure during synaptogenesis produces high levels of anxiety-like traits and decreased memory performance. Alcohol-exposed mice (and matched unexposed controls) were put in 'environmentally-enriched' conditions of voluntary exercise, physical activities and cognitive stimulation to ascertain the effects of a positive postnatal environment. The results show that …

Investigating The Protective Effects Of Telomerase Reverse Transcriptase On Neuronal Metabolism And Resistance To Amyloid-Beta, Olivia Singh

Electronic Thesis and Dissertation Repository

Maintenance of telomere length during cell division is dependent on the catalytic subunit telomerase reverse transcriptase (TERT), which adds TTAGGG repeats to the ends of chromosomes to prevent telomere shortening during DNA replication. However, non-telomeric roles of TERT have emerged under oxidative stress whereby TERT translocates from the nucleus to the mitochondria and protects against mitochondrial dysfunction through a poorly defined mechanism. A major pathological feature of Alzheimer’s Disease (AD) is the progressive accumulation of amyloid-beta (Aβ) peptide within the cortex and hippocampus. Aβ can directly interfere with mitochondrial respiration and promote mitochondrial dysfunction, ROS production, and neuronal cell death. …

Conditional Sox9 Ablation 30 Days After Spinal Cord Injury: Testing The Therapeutic Value Of A Successful Acute Strategy To Increase Neuroplasticity In A Model Of Chronic Spinal Cord Injury, Natalie M. Ossowski

Electronic Thesis and Dissertation Repository

Many individuals who have suffered from spinal cord injury (SCI) have longstanding damage. The molecular environment of the spinal cord is not permissive to axonal growth and neuroplasticity after injury is limited. Perineuronal nets containing chondroitin sulfate proteoglycans (CSPGs) are major inhibitors of axonal sprouting. Our laboratory has identified that the transcription factor SOX9 regulates a battery of genes involved in CSPG biosynthesis. Using Sox9 conditional knockout mice, we have shown that ablating Sox9 before injury decreases CSPG levels in the cord, increases reparative sprouting, and leads to improved locomotor recovery. However, it is unknown whether Sox9 ablation following SCI …

Prefrontal Cortex Dopamine Transmission Regulates Emotional Memory Processing And Morphine Reward Salience: Implications For Post-Traumatic Stress Disorder And Addiction Comorbidity, Jing Jing Li

Electronic Thesis and Dissertation Repository

Post-Traumatic Stress Disorder (PTSD) and addiction are strongly comorbid. However, the underlying neural mechanisms by which traumatic memory recall may increase addiction liability are poorly understood. The inability to suppress memory recall related to either stressful or rewarding, drug-related experiences may be an underlying neuropsychological feature capable of triggering both PTSD or addiction-related behaviours. Our previous research has shown that transmission through dopamine (DA) D₄ and D₁ receptor subtypes (D₄R, D₁R) within the prefrontal cortex (PFC) strongly modulates emotional memory acquisition and recall (Lauzon et al., 2009). Using olfactory fear conditioning and morphine conditioned …

Pore-Lining Residues And Intracellular Magnesium Concentration Influence Connexin50 Gap Junction Unitary Channel Conductance, Mary Grace M. Tejada

Electronic Thesis and Dissertation Repository

Gap junction (GJ) channels mediate direct intercellular communication. Each GJ channel consists of two hemichannels and each hemichannel is a hexamer of connexins. GJs formed by different connexins display different unitary channel conductance (γ_j) and intracellular magnesium modulation. The underlying mechanisms are not fully clear. The present study investigates the effect of mutating putative pore-lining residues (G8, G46, and V53 individually or together) into glutamate in Cx50 on homotypic GJ channel properties. Expression of the triple and individual mutants in GJ-deficient N2A cells resulted in the formation of functional GJ channels similar to that of Cx50 GJs. However, …

Synaptic Mechanisms For The Hypothalamic-Pituitary-Adrenal Axis Activation By Prostaglandin E2, Zahra Khazaeipool

Electronic Thesis and Dissertation Repository

The activation of the hypothalamic-pituitary-adrenal (HPA) axis during inflammation is mediated by prostaglandin E2 (PGE2) produced in the brain. However, how PGE2 recruits neuronal mechanisms for HPA axis activation remains unknown. Accumulating evidence indicates that GABA-mediated inhibitory synaptic transmission plays a major role in the HPA axis regulation. That is, GABAergic transmission constitutively constrains the excitability of parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus of the hypothalamus (the HPA axis output neurons); the removal from this inhibition (i.e. disinhibition) powerfully activates the HPA axis. My thesis examined the actions of PGE2 on GABAergic synaptic transmission to PNCs. Using patch …

Cerebral Lactate Metabolism And Memory: Implications For Alzheimer's Disease, Richard Andrew Harris

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques that are comprised of aggregated amyloid-beta peptides. These toxic proteins promote mitochondrial dysfunction and neuronal cell death. A shift in metabolism away from oxidative phosphorylation and toward aerobic glycolysis, with the concomitant production of lactate, affords neurons a survival advantage against amyloid-beta toxicity. Recent evidence now suggests that aerobic glycolysis in the brain plays a critical role in supporting synaptic plasticity, learning, and memory. However, the role of aerobic glycolysis and lactate metabolism in AD-mediated cognitive decline is unknown. My objective was to test the hypotheses that aerobic glycolysis …

Regulation Of Human 69-Kda Choline Acetyltransferase Protein Stability And Function By Molecular Chaperones And The Ubiquitin-Proteasome System, Trevor M. Morey

Electronic Thesis and Dissertation Repository

The enzyme choline acetyltransferase (ChAT) mediates synthesis of the neurotransmitter acetylcholine required for cholinergic neurotransmission. ChAT mutations are linked to congenital myasthenic syndrome (CMS), a rare neuromuscular disorder. One CMS-related mutation, V18M, reduces ChAT enzyme activity and cellular protein levels, and is located within a highly-conserved N-terminal proline-rich motif at residues ₁₄PKLPVPP₂₀. It is currently unknown if this motif regulates ChAT function. In this thesis, I demonstrate that disruption of this proline-rich motif in mouse cholinergic SN56 cells reduces both the protein levels and cellular enzymatic activity of mutated P17A/P19A- and V18M-ChAT. The cellular loss …