Browsing by Subject "Pyramidal Cells"
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Item Brain-Region-Specific Contributions of FOXP1 to Autism and Intellectual Disability Phenotypes(2017-08-11) Araujo, Daniel John; Eisch, Amelia J.; Konopka, Genevieve; Powell, Craig M.; Volk, Lenora J.; Wu, Jiang I.Mutations and deletions in the transcription factor FOXP1 are causative for severe forms of autism spectrum disorder (ASD) that are often comorbid with intellectual disability (ID). FOXP1 is enriched throughout the brain, with strong expression in the pyramidal neurons of the neocortex, the CA1/CA2 subfields of the hippocampus, and the medium spiny neurons of the striatum. Understanding the role that FOXP1 plays within these brain regions could allow for management of ASD and ID symptoms. This doctoral dissertation leverages multidisciplinary techniques and Foxp1 mutant mouse models to ascertain the role of Foxp1 in the brain and its contribution to specific ASD- and ID-relevant phenotypes. In the first chapter of this dissertation, I review the literature on the characteristics, demographics, and shared genetic underpinnings of ASD and ID and I review the work linking FOXP1 to these disorders. Afterwards, I describe the regional transcriptome regulated by Foxp1 within the brain and I correlate alterations in the gene expression profile of the striatum with deficits in communication (Chapter 2). Briefly, I utilized RNA-sequencing performed on Foxp1 heterozygous knockout animals to uncover the genes regulated by Foxp1 within the neocortex, hippocampus, and striatum. I also recorded the early postnatal ultrasonic vocalizations (USVs) of these animals and I was able to correlate changes in the properties of striatal medium spiny neurons with deficits in USV production. Next, I move onto using a Foxp1 conditional knockout (Foxp1cKO) mouse model to ascertain the contributions of Foxp1 in the neocortex and the hippocampus to ASD and ID-related behaviors (Chapter 3). In brief, I show that total loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/2 hippocampal subfields results in social communication deficits as well as hyperactivity and anxiety-like behaviors. I also show that Foxp1cKO mice display gross impairments in hippocampal-based spatial-learning tasks and I correlate these deficits with alterations in the expression of genes involved in hippocampal physiology and synaptic plasticity. In my final chapter (Chapter 4), I consider the implications that these data have on our understanding of the role that Foxp1 plays within the brain and I suggest research strategies to answer the new questions that my findings have generated. I also discuss the implications that this research has on our understanding of ASD and ID pathophysiology in general and I recommend future directions for work focused on managing these disorders.Item The Role of MEF2 Transcription Factors in Neocortical Circuit and Synapse Development In Vivo(2016-08-10) Rajkovich, Kacey Elise; Konopka, Genevieve; Huber, Kimberly M.; Powell, Craig M.; Roberts, Todd; Gibson, Jay R.Proper neocortical circuit development requires postnatal experience and transcription. Neocortical neurons migrate to their proper layers and then undergo robust synapse proliferation to maximize contacts with presynaptic partners. Synapses are dynamic structures subjected to an equilibrium of formation and elimination rates to preserve meaningful and prune superfluous synapses, respectively. A neuron receives heterogeneous inputs and must tightly regulate connectivity with distinct presynaptic entities. Dysregulated connectivity causes aberrant circuit function and ultimately abnormal behavior linked with neurodevelopmental disorders such as autism. Therefore, a neuron must contain cellular machinery to regulate synaptic connectivity. The activity-dependent Myocyte Enhancer Factor-2 (MEF2) transcription factors - MEF2A-D - have distinct but overlapping expression profiles throughout the brain and typically suppress synapse number. The cell-autonomous role for specific MEF2 genes in neocortical circuit development has never been explored. Furthermore, a link between MEF2 and experience has never been identified within the neocortex. Lastly, whether MEF2 transcription factors regulate specific synaptic pathways is unknown. I report that MEF2A, MEF2C, and MEF2D non-redundantly regulate synapse development onto individual pyramidal neurons within layers 2 and 3 (L2/3) of the postnatal mouse primary somatosensory "barrel" cortex in vivo. Simultaneous deletion of Mef2a and Mef2d modestly decreases spontaneous glutamatergic synaptic transmission in comparison to neighboring control L2/3 neurons. MEF2C, however, cell-autonomously mediates several unique aspects of L2/3 circuit development at a postsynaptic locus. Sparse Mef2c deletion decreases excitatory synapse number onto basal dendrites of L2/3 neurons targeted by local inputs. Therefore, Mef2c promotes excitatory synapse formation and/or maintenance in neocortex. Additionally, MEF2C and sensory experience interact to promote strength of local L2/3 inputs. Mef2c deletion depresses these local inputs in spared barrel cortices comparably to the depression induced by sensory deprivation via whisker trimming onto wildtype (WT) L2/3 neurons; hence MEF2C is required for experience-dependent development of L2/3 circuitry. Lastly, MEF2C differentially suppresses long-range intercortical while promoting connectivity at local L2/3 synaptic input pathways. These data represent novel mechanisms through which MEF2C regulates neocortical synapse development in vivo and provides insight into how activity-dependent transcription within the nucleus interacts with experience to alter specific synapse populations at the neural plasma membrane.