R01MH130356

Effects of 16p11.2 copy number variation on neuronal development and pathology - project summary/abstract

Copy number variations (CNVs) of the human 16p11.2 genetic locus, containing 29 coding genes, are associated with a number of neurodevelopmental and psychiatric disorders. The deletion (16pdel) and duplication (16pdup) variants of this region have poorly understood pleiotropic effects. Although autism is more common in patients with deletions, and schizophrenia is more common in those with duplications, underlying mechanisms are not clear.

Several molecular pathways from the 16p11.2 region modulate neuronal differentiation, migration, axonal development, and synapse formation, as well as energy and lipid metabolism. Studies of 16p-animal models have suggested deficits in the KCTD13-RHOA pathway activation, neuronal migration, axonal development, and behavior. In turn, disruption of ceramide homeostasis due to 16p11.2 CNVs at FAM57B locus altered lipid abundance, cell membrane dynamics, synaptic protein expression, and synaptic transport, suggesting that lipidome dysregulation could contribute to neuronal function and activity. However, the exact molecular mechanisms underlying these neuronal dysfunctions in excitatory versus inhibitory neurons are lacking. Moreover, contradictory results have been reported from different animal and human cell models.

To address this gap of knowledge, we developed human iPSC-derived neuronal models of 16p11.2 CNVs and demonstrated that i) KCTD13 regulates RHOA pathway activation, and increased RHOA expression leads to hyperactivity of the 16pdel human cortical neuron networks, and ii) there are significant changes in key mitochondrial and lipid enzyme transcripts, including decrease in FAM57B-mediated ceramide synthase expression, that directly correlate with observed changes in the metabolome and lipidome. These data suggest that 16pdel leads to complex metabolic disruptions and deficient ceramide expression that might contribute to the observed functional neuronal network phenotypes.

These data have led us to hypothesize that 16p11.2 CNVs cause dysregulation of ceramide abundance in glutamatergic and GABAergic neurons that in turn promotes deficits in synaptic development and function leading to network disorganization and hyperactivation. Here, we will investigate this hypothesis and the effects of 16p11.2 CNVs on cortical neuron development and function in human iPSC-derived 2-dimensional excitatory-inhibitory neuron co-cultures and human iPSC-derived 3-dimensional forebrain organoids.

To reduce variability caused by different genotypic backgrounds, we will study CRISPR-Cas9 induced 16p11.2 CNV iPSC lines in addition to iPSC lines derived from patients and healthy controls. We will utilize state-of-the-art molecular methodologies to uncover mechanisms underlying the synaptic dysfunction of the excitatory-inhibitory neurons in 16p11.2 CNVs, including single cell transcriptional gene expression profiling and lipidome/metabolome profiling. Finally, we will investigate the excitatory-inhibitory network function, connectivity, and oscillation patterns with multi-electrode arrays and patch clamping.

We anticipate that this study will uncover new molecular targets related to cortical neuron dysfunction in 16p11.2 CNV disorders.

Children's Hospital Corporation

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. WE FULFILL THIS MISSION BY SUPPORTING AND CONDUCTING RESEARCH ON MENTAL ILLNESSES, HEALTH SERVICES, AND THE UNDERLYING BASIC SCIENCE OF THE BRAIN AND BEHAVIOR; SUPPORTING THE TRAINING OF SCIENTISTS TO CARRY OUT BASIC AND CLINICAL MENTAL HEALTH RESEARCH; AND COMMUNICATING WITH SCIENTISTS, PATIENTS, PROVIDERS, AND THE PUBLIC ABOUT MENTAL HEALTH RESEARCH ADVANCES AND PRIORITIES. IN MAY 2024, NIMH RELEASED ITS STRATEGIC PLAN FOR RESEARCH. THE STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH.THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTES RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Boston, Massachusetts 021155724 United States

Single Zip Code

Cellular and Molecular Biology of Complex Brain Disorders (R01 Clinical Trial Not Allowed) (PAR-20-263)

Amendment Since initial award the total obligations have increased 86% from $1,723,144 to $3,207,660.