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- All Subjects: Stress
- All Subjects: Synaptic transmission
Description
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delays, intellectual disabilities, impaired language and speech, and movement defects. Most AS cases are caused by dysfunction of a maternally-expressed E3 ubiquitin ligase (UBE3A, also known as E6 associated protein, E6-AP) in neurons. Currently, the mechanism on how loss-of-function of the enzyme influences the nervous system development remains unknown. We hypothesize that impaired metabolism of proteins, most likely those related to E6-AP substrates, may alter the developmental trajectory of neuronal structures including dendrites, spines and synaptic proteins, which leads to disrupted activity/experience-dependent synaptic plasticity and maturation. To test this hypothesis, we conducted a detailed investigation on neuronal morphology and electrophysiological properties in the prefrontal cortex (PFC) layer 5 (L5) corticostriatal pyramidal neurons (target neurons). We found smaller soma size in the maternal Ube3a deficient mice (m-/p+; 'AS' mice) at postnatal 17-19 (P17-19), P28-35 and older than 70 days (>P70), and decreased basal dendritic processes at P28-35. Surprisingly, both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) decreased on these neurons. These neurons also exhibited abnormalities in the local neural circuits, short-term synaptic plasticity and AMPA/NMDA ratio: the excitatory inputs from L2/3 and L5A, and inhibitory inputs from L5 significantly reduced in AS mice from P17-19; Both the release probability (Pr) and readily-releasable vesicle (RRV) pool replenishment of presynaptic neurons of the target neurons were disrupted at P17-19 and P28-35, and the change of RRV pool replenishment maintained through adulthood (>P70). The AMPA/NMDA ratio showed abnormality in the L5 corticostriatal neurons of PFC in AS mice older than P28-35, during which it decreased significantly compared to that of age-matched WT littermates. Western Blot analysis revealed that the expression level of a key regulator of the cytoskeleton system, Rho family small GTPase cell division control protein 42 homolog (cdc42), reduced significantly in the PFC of AS mice at P28-35.These impairments of synaptic transmission and short-term synaptic plasticity may account for the impaired neuronal morphology and synaptic deficits observed in the PFC target neurons, and contribute to the phenotypes in AS model mice. The present work reveals for the first time that the E6-AP deficiency influences brain function in both brain region-specific and age-dependent ways, demonstrates the functional impairment at the neural circuit level, and reveals that the presynaptic mechanisms are disrupted in AS model. These novel findings shed light on our understanding of the AS pathogenesis and inform potential novel therapeutic explorations.
ContributorsLi, Guohui (Author) / Qiu, Shenfeng (Thesis advisor) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2017
A Role for SIRT-1 in Dendritic and Spine Morphology of Medium Spiny Neurons in the Nucleus Accumbens
Description
Major depressive disorders affect 350 million people globally and are the leading cause of disability worldwide. Chronic or prolonged stress can trigger development of depression. Key symptoms of depression are anhedonia, helplessness, and decreased socialization. These behavioral outcomes suggest a dysfunction within the brain’s reward system, the mesolimbic system. The nucleus accumbens (NAc) is regarded as the brain’s reward hub, integrating signals from multiple brain regions to influence motivated behavioral output. The NAc consists of medium spiny neurons (MSNs) which represent 95% of the cellular landscape. These neurons can be separated into two distinct groups, dopamine receptor-1 (DR1 or D1) and dopamine receptor-2 (DR2 or D2). Differentiating between these two cell types is ideal as activation results in opposing outcomes. One protein of interest sirtuin-1 (SIRT1) has been found to alter dendritic morphology in brain regions involved in stress. Discovery that SIRT1, a histone deacetylase (HDAC), has cell-type-specific action in the NAc in a mouse model of depression and resulting behavioral changes suggest possible underlying morphological changes. Neuronal morphology includes measurement of the dendritic arbor and dendritic spines, small protrusions from the dendritic shaft. These studies seek to elucidate morphological changes following knockout or overexpression of SIRT1 in either D1-or D2-MSNs in both male and female mice. Results show that SIRT1 overexpression in male D1-MSNs results in a significant increase in stubby spines and a decrease in mushroom spines. Conversely, in female mice with SIRT1 OVEXP in D1-MSNs, there was found a significant increase in mushroom spines accompanied by a significant decrease in stubby spines. The D2-targeted mice also showed significant changes across spine types. In both treatment types, D2- males had a significant increase in stubby spines, filopodia, and thin spines. Females with SIRT1 knocked out had a significant decrease in filopodia and thin spines. SIRT1 overexpression in D2- females showed a significant decrease in stubby spines. These results suggest SIRT1 has a regulatory role in the density of spine type and possibly the maturation of spines. This discovery of an increase in stubby spines in male D1-MSNs overexpressing mice establishes a role for SIRT1 in stubby spine formation.
ContributorsCall, Tanessa (Author) / Ferguson, Deveroux (Thesis advisor) / Neiswander, Janet (Thesis advisor) / Hammer, Ron (Committee member) / Qiu, Shenfeng (Committee member) / Arizona State University (Publisher)
Created2022