Browsing by Subject "Schizophrenia"

Schizophrenia is marked by significant disruptions to dopaminergic signaling across the mesolimbic and mesocortical circuits. Antipsychotic drugs have been largely unsuccessfully treating cognitive symptoms that debilitate the schizophrenia patient population. Dopamine 2 Receptor (D2R)- βeta arrestin 2 (βarr2) biased signaling, independent of the canonical G protein signaling, has emerged as a potential mechanism for antipsychotic drugs to restore dopaminergic signaling and improve treatment resistant cognitive symptoms. In the following experiments, I described gene editing tools to systematically investigate D2R signaling in a region or cell specific manner. Next, I evaluated the behavioral effects of two functionally selective D2-like βarr2 biased ligands against psychotomimetic challenge from phencyclidine or amphetamine. Then I employed chemogenetics to perform synthetic pharmacology experiments e.g. studying the signaling cascade of a drug without using the drug, to discover how D2- R βarr2 signaling produces antipsychotic effects in the prefrontal cortex. Lastly, I characterized the neurophysiological changes induced by phencyclidine and a D2R βarr2 biased ligand within relevant brain regions in the meso -limbic and -cortical circuits. Our results determined antipsychotic like activity is 1) regulated by excitation-inhibitory balance maintained by cortical GABA interneurons 2) dependent on βarr2.

G-protein coupled receptors (GPCRs) are pivotal to multiple physiological processes, including neuronal functions such as neurotransmission and memory formation. Consequently, aberrant GPCR signaling has been implicated in complex psychiatric disorders. Our ability to develop efficient therapeutic strategies depends on our understanding of the molecular factors that govern GPCR activity. We performed a genome-wide CRISPR interference screen using a fluorescent cAMP-dependent transcriptional reporter and identified 95 novel regulators that had no previous connection to the GPCR/cAMP pathway. We functionally validated eight regulators and showed that they control distinct steps of the pathway. One of these, RNA binding motif 12 (RBM12), is a novel potent negative regulator of the GPCR/cAMP pathway. Truncating RBM12 mutations are implicated in highly penetrant schizophrenia and defective brain development, yet its cellular function is unknown. To investigate its role in GPCR/cAMP signaling, we performed CRISPR-based gene editing in two complementary cellular models: experimentally tractable HEK293 cells and physiologically relevant human induced pluripotent stem cell-derived neurons. We found that RBM12 deficiency leads to hyperactive cAMP accumulation, PKA activity, and downstream CREB-dependent transcriptional responses in response to the activation of stimulatory GPCRs with key functions in neurobiology (beta-adrenergic, dopamine, and adenosine). We observed that the cAMP signaling and PKA activity are independently subject to regulation by RBM12. This signaling hyperactivity is conserved in the two cellular model systems. We further show that schizophrenia-associated truncating RBM12 mutations (c.2377G>T and c.2532delT) failed to rescue the signaling hyperactivation due to possible loss-of-function and protein stability defect. In agreement with its activity as an RNA-binding protein, we show that RBM12 depletion led to altered expression of genes with established roles in the signaling pathway, including an upregulation of cyclases and the protein kinase A catalytic subunits as well as a downregulation of phosphodiesterases. In addition, we observed aberrant gene expression in neurogenesis, neurodevelopment, and differentiation pathways. Together, these experiments provide critical insights into this uncharacterized gene and its function as a novel regulator of GPCR signaling. By uncovering the novel regulatory role of a schizophrenia-risk gene in GPCR signaling, we expand our understanding of the molecular basis of neuropsychiatric disorders and enable the identification of novel druggable targets.

Background: Hopefulness is a positive orientation or state of mind that can aid in the recovery and treatment for mental illness, as it can have significant impacts on clinical and psychosocial outcomes. As resource-constrained settings work to implement recovery-oriented care, there is a need to better understand hopefulness among people living with schizophrenia (PLWS) and caregivers in their extended family networks. This study seeks to examine the dyadic relationship of hopefulness and its associated correlates among PLWS and their caregivers in Tanzania. Methods: This study utilized longitudinal data collected as part of a randomized controlled trial testing a culturally-tailored model of Family Psychoeducation in Tanzania. The Herth Hope Index was used to measure hopefulness among PLWS and their caregivers at baseline and three months post-intervention. Univariable and multivariable regression models were conducted to determine correlates of hopefulness at baseline, while the Actor-Partner Interdependence Model (APIM) was employed to examine the longitudinal, dyadic relationship of hopefulness among PLWS and their caregivers. APIM can help determine how an individuals’ level of hope at time 0 impacts his or her own level of hope at time 1 and their partner’s level of hope at time 1. Results: For PLWS and their caregivers, actor effects were less than one (PLWS, β=0.261; caregivers, β=0.318), indicating stability in hopefulness over time. Regarding partner effects, caregivers baseline hopefulness had a positive effect on PLWS hopefulness at follow-up (β=0.100). This indicates that higher caregiver hope at time 0 is associated with higher levels of hope in PLWS at time 1. Baseline hopefulness levels for PLWS had a negative effect on caregiver hopefulness at follow-up (β= -0.106). This suggests that higher PLWS hope at time 0 is associated with lower levels of hope in caregivers at time 1. Conclusions: Hopefulness seems to be interesting to consider because caregiver hopefulness can influence improvements in patient hopefulness over time. Future studies should further explore the dyadic relationship of hopefulness in this population, as hope is a non-pharmacological mechanism of change that is underutilized globally.

Schizophrenia is a complex and debilitating psychiatric illness characterized by positive symptoms like hallucinations and delusions and negative symptoms like blunting of affect, avolition, and poverty of thought. This constellation of symptoms is hypothesized to result from dopaminergic dysfunction, glutamatergic dysfunction, and dysfunctional stress-reactivity. Prior to the onset of schizophrenia there is a prodromal period when individuals begin to experience sub-clinical symptoms and decreased functioning. This period is important to study not only to help elucidate biologic mechanisms of the illness but also to potentially alter the course of the illness through early treatment. The difficulty of studying this period lies in its recognizing it prospectively. To address this researchers have begun to study the at-risk mental state, a state that is associated with a high but not inevitable risk of conversion to psychosis. The studies described in this dissertation are aimed at a neurofunctional characterization of the at-risk mental state in three primary domains: reward-anticipation, hippocampus-dependent learning, and stress-reactivity. Individuals at-risk for psychosis and age-matched healthy volunteers underwent functional magnetic resonance imaging while performing tasks targeting these domains. In the reward-anticipation task, at-risk individuals showed decreased ventral tegmental area (VTA) and dorsolateral prefrontal cortex (DLPFC) responses to reward anticipation. In the hippocampus-dependent learning task, at-risk individuals showed deficits in hippocampus-dependent memory, decreased VTA engagement, and increased DLPFC activation during learning of associations between items. In the stress-reactivity task, at-risk individuals showed increased activation in the bed nucleus of the stria terminalis/basal forebrain (BNST), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in response to neutral faces. Collectively, these experiments show that neurofunctional deficits in reward-anticipation, hippocampus-dependent learning, and stress-reactivity are present in the putative prodrome, prior to the onset of psychosis. Regions implicated are those that would be expected based on current models of schizophrenia and neurofunctional studies in those with frank psychosis.

Background: Deinstitutionalization of persons with schizophrenia has led to families providing the majority of care and carrying the bulk of burden. There is a need to identify factors that influence caregiver burden in order to properly address the needs of caregivers. This is particularly important in low-resource settings, where psychiatric services are scarce and interventions for schizophrenia could be most effective if targeted to the affected individual and their caregiver. This study seeks to examine the association between family functioning and perceived burden in informal caregivers of individuals with schizophrenia in Tanzania and identify socio-demographic and illness-related factors that may be associated with caregiver burden in the study population.Methods: This study analyzed cross-sectional data from 65 dyads of individuals with schizophrenia and their informal caregivers in Dar es Salaam and Mbeya, Tanzania. Caregiver burden was measured using the Burden Assessment Scale (BAS). Univariable and multivariable regression analyses were performed to determine the relationship between perceived caregiver burden and family functioning and explore correlates of burden among caregivers. Results: Sixty-three percent of caregivers in our study reported experiencing high burden as a result of caring for a relative with schizophrenia. Multivariable regression analyses revealed that poor family functioning was a significant correlate of high caregiver burden (OR = 4.79; 95% CI = 1.19, 19.32). Additionally, caregiver having worked in the past 3 months was associated with high caregiver burden (OR = 4.80; 95% CI = 1.14, 20.23), while higher levels of hope in the caregiver were associated with low caregiver burden (OR = 0.82; 95% CI = 0.70, 0.95). Although not included in the multivariable regression model, another factor that was linked to high caregiver burden was caring for a woman with schizophrenia (OR = 3.91; 95% CI = 1.13, 13.50). Conclusions: We found that poor family functioning, caregiver having worked in the past 3 months, lower levels of hope in the caregiver, and caring for a woman with schizophrenia were correlates of high caregiver burden. Future interventions aiming to reduce caregiver burden may benefit from improving family functioning and nurturing hope among caregivers of individuals living with schizophrenia. We must pay special attention to the needs of caregivers that work in addition to providing care for a relative with schizophrenia in order to better support them.