Neurotrophic Theory of Accelerated Temporal Cortex Maturation in the Valproic Acid Rat Model of Autism
Creators: name: Hung, Johanna
Publisher: name: Graduate Studies
Year: 2014
Subjects: subject: Neuroscience
subject: Neuroscience

description: Neuronal networks in the human ventro-anterior temporal lobe play a critical role in mediating object perception, long term semantic memory and social communication. A unique feature of this region is its delayed acquisition of peak cortical thickness, which is not reached until the second decade of life. In the majority of individuals with Autism Spectrum Disorders (henceforth referred to as autism) there is premature overgrowth of the temporal lobe during childhood. In this thesis, I studied the maturation trajectory of neurons from a homologous region in the albino rat, the posterior temporal association cortex (TeA), and how it is altered with exposure to the autism-linked teratogen valproic acid (VPA). My overarching hypothesis was that the slow maturation of TeA neurons during the first three weeks of postnatal development is a result of low local production and/or secretion of brain derived neurotrophic factor (BDNF), and that VPA can accelerate maturation of TeA neurons during this period by prematurely increasing BDNF signalling. Chapter 1 is a general introduction that describes the importance of the temporal association cortex in cognitive development and autism research (Section 1.1), the phenomenon of slow maturation of heteromodal association cortices in humans (Section 1.2), the anatomy, function and development of the rat cortex (Section 1.3 and 1.4), and the rodent VPA model of autism (Section 1.5). The aim of the introduction is to clearly define the context, significance, and rationale for the thesis hypothesis and aims, which are summarized in Section 1.6. Materials and methods used in this thesis are presented in Chapter 2. Chapters 3-7 are the results of experimental work. These chapters are ordered to provide a general characterization of neuroanatomy of the TeA in normal and VPA treated animals in intact brains, before moving into increasingly mechanistic investigations using primary neuronal cultures. In Chapter 3, I compare the cortical thickness trajectory of the TeA with that of other cortical regions. In Chapter 4, I show that VPA increases the cortical thickness and density of Golgi-Cox stained processes in the TeA and that this may have behavioural consequences. In Chapter 5, I report that TeA neurons grow slowly in vitro as they do in vivo. Maturation of TeA neurons lagged behind that of primary sensorimotor areas and the hippocampus as measured by single-cell morphometry, dendrite density, and electrophysiology. These data suggest that endogenous properties are essential for regulating neuronal maturation rate. In Chapter 6, I describe my investigations of the effect of VPA on TeA maturation using the cell culture paradigm. VPA increased dendrite density in TeA and entorhinal cortex cultures but not those prepared from frontal association cortex, parietal association cortex, hippocampus, or primary sensorimotor cortices of the temporal, parietal and occipital lobes. VPA exposure also increased the percentage of spiking neurons in TeA cultures. These results suggest that TeA and EC cultures are intrinsically different from the other cortical areas examined. In Chapter 7, I investigated the mechanism by which TeA neurite outgrowth was selectively enhanced after VPA treatment. I found that the TeA normally has a significantly lower level of brain-derived neurotrophic factor (BDNF) immunostaining than many other brain regions during the early postnatal period. VPA exposure increased the intensity of BDNF staining in cultured TeA neurons, and its effect on dendrite growth was blocked by the specific tropomyosin-receptor kinase B (trkB) inhibitor ANA-12. Direct application of BDNF to TeA cultures reproduced the effect of VPA on neuronal morphology. Based on the results presented in this thesis and existing literature, I propose a hypothesis about the mechanism of slow TeA maturation and the developmental pathology of autism, presented in Chapter 8 along with a discussion of the mechanism by which VPA increases BDNF expression.