Social isolation during adolescence can have long lasting negative effects in both humans and animal models. In mice, post-weaning social isolation leads to increased addiction-like behaviors in adulthood. However, little is known about how post-weaning social isolation alters the brain. Stress during development can lead to persistent restructuring of neurons. Changes in dendritic spines can be long-lasting and have been theorized to play an important role in the maintenance of cocaine craving. We found that post-weaning isolation led to a persistent increase in spine density in adulthood within both the core and shell regions of the nucleus accumbens in male mice, but not female mice. In contrast, in the infralimbic cortex, post-weaning social isolation led to an increase in spine density only in female mice. This study highlights the long-lasting, sex-specific effects of post-weaning isolation. Microglia have been shown to assist in both the formation and elimination of dendritic spines, and are activated following exposure to stress and cocaine. Therefore, we hypothesized that microglia may be involved in the restructuring of dendritic spines during post-weaning isolation, and contribute to addiction-like behavior in adulthood. We examined whether inhibiting microglia with minocycline during the first three weeks of post-weaning isolation altered the impact of isolation in cocaine seeking. Isolated animals that received minocycline showed increased cocaine seeking in adulthood compared to group housed mice and isolated mice that received saline. Minocycline and isolation also caused sex-specific alterations in spine density. The findings of these studies provide insight into the mechanisms by which social isolation during adolescence increases vulnerability to addiction later in life. / Psychology

No description available.

Neurodevelopmental disorders (NDDs) are a heterogeneous set of disorders that are characterized by early disruptions to brain development and include autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), developmental delay (DD), intellectual disability (ID), epilepsy and schizophrenia (SZ). Although thousands of genetic risk variants have been identified, there is a lack of understanding of how they impact cellular and molecular mechanisms that underlie the clinical presentation and heterogeneity of NDDs. To investigate this, we used a combination of cellular, molecular, bioinformatic and omics methods to study NDD-associated molecular pathways in distinct neuronal populations. First, we studied the interaction between the high-confidence SZ risk genes DISC1 and NRG1-ErbB4 in cortical inhibitory neurons and found that NRG1-ErbB4 functions through DISC1 to regulate dendrite growth and excitatory synapses onto inhibitory neurons. Next, we studied the 15q13.3 microdeletion, a recurrent copy number variation (CNV) that is associated with multiple NDDs. Using a heterozygous mouse model [Df(h15q13)/+] and human sequencing data we identified OTUD7A (encoding a deubiquitinase) as an important gene driving neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome. Due to the paucity of literature on the function of OTUD7A in the brain, we used a proximity-labeling approach (BioID2) to elucidate the OTUD7A protein interaction network (PIN) in cortical neurons, and to examine how patient mutations affect the OTUD7A PIN. We found that the OTUD7A PIN was enriched for postsynaptic and axon initial segment proteins, and that distinct patient mutations have shared and distinct effects on the OTUD7A PIN. Further, we identified the interaction of OTUD7A with a high-confidence bipolar risk gene ANK3, which encodes AnkyrinG. We identified decreased levels of AnkyrinG in Df(h15q13)/+ neurons, and synaptic phenotypes were rescued by increasing AnkyrinG levels or targeting the Wnt pathway. Future investigation should include examination of the role of OTUD7A deubiquitinase activity in neural development. / Dissertation / Doctor of Philosophy (PhD) / Neurodevelopmental disorders result from disruptions to early brain development and include autism spectrum disorder (ASD), developmental delay (DD), epilepsy, and schizophrenia (SZ). These disorders affect more than 3% of children worldwide and can have a significant impact on an individual’s quality of life, including an increased risk of death in some cases. There is currently a lack of understanding of how these disorders develop and how to effectively treat them. Neurodevelopmental disorders are thought to arise from alterations in the connections between brain cells (neurons) and one of the major risk factors for these disorders is having certain variations in regions of the genome (DNA sequences), with more than 1000 of these risk variants having been identified so far. In this thesis, we analyzed how genetic risk factors interact in neurons to regulate neural connectivity. We discovered that risk variants found in individuals with different disorders actually work together to regulate similar processes important for neural connectivity, which suggests that distinct disorders may share a common underlying cause. Additionally, we established the importance of a new ASD risk gene and discovered that it interacts with other known risk genes to regulate neural connectivity. This thesis provides new insights into the processes in the brain that lead to neurodevelopmental disorders and has implications for future development of effective therapies for individuals affected by these disorders.

No description available.

Autism spectrum disorders (ASDs) are a diverse class of neurodevelopmental disorders with various aberrant cellular phenotypes such as dysfunctional neurotransmission and irregular neuronal morphology. ASDs have a broad underlying genetic background with many genes linked to their etiology. UBE3A has been identified as a top gene candidate associated with ASD, and overexpression of UBE3A via copy-number variation confers hallmark ASD behaviors in humans and transgenic mice. Our previous work revealed that synapse formation was negatively affected in the Ube3A-ASD mouse model (Ube3A 2X Tg, or simply “2X Tg”). However, the cellular and molecular mechanisms underlying the synaptic dysregulation remain unknown. We sought to identify a cell-type specific mechanism by which these morphological changes were conferred. We found that selective overexpression of Ube3A in neurons failed to induce changes in dendritic spine maturation. In contrast, overexpression of Ube3A in astrocytes resulted in alterations in spines and synapses. Further, we identified thrombospondin-2 (TSP2), a secreted astrocytic glycoprotein promoting synaptogenesis and spinogenesis, is involved in the defective spine maturation. Ube3A overexpression confers a loss of transcriptional down-regulation of TSP2 in astrocytes, and the medium of astrocyte cultures with Ube3A overexpression was sufficient to trigger spine changes similar to that observed in mixed cultures that globally overexpress Ube3A. Importantly, depletion of TSP2 promoted similar loss of dendritic spine maturation, whereas supplement of TSP2 to 2X Tg astrocyte media was able to rescue the spine defects. Furthermore, overexpression of Ube3A in an astrocyte-specific manner recapitulated aberrant dendritic spine maturation as well as autism-like behaviors displayed in 2X Tg mice. Collectively, these findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels.

No description available.

No description available.

No description available.

No description available.

No description available.