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Principal Investigator: Kimberly Frances Raab-Graham
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2020
Award: $88,123
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Overview: The project focuses on understanding the molecular basis of how disrupted calcium homeostasis
leads to disrupted hippocampal network activity that results in maladaptive responses in neurons with TSC
deficient signaling.
Approximately 33% of children who have autism spectrum disorder (ASD) also have epilepsy. Early childhood
seizures can result in compromised synaptic plasticity and cognitive impairment, suggesting that the
hippocampus may be vulnerable to changes in network excitability. Despite the importance of this problem, the
connection between seizure activity and development of ASD is poorly understood. Mammalian Target of
rapamycin (mTOR) is a kinase that regulates protein synthesis and is overactive in many complex brain
disorders. In the proposed studies, we focus on a mouse model of ASD, Tuberous Sclerosis Complex (TSC),
which is a disorder that results from mutations in either the tsc1 or 2 genes. We propose that deficient TSC
signaling leads to overactive mTOR and deficient protein synthesis that manifests as epilepsy and ASD. There
is no cure for TSC, treatments are limited, and new therapeutic targets are needed. Our previous work has
demonstrated that mTOR activity represses the expression of epilepsy-linked ion channels. The proposed
studies extend our work to address the molecular mechanisms underlying hippocampal network
hyperexcitability in TSC. We will take a multidisciplinary approach to critically test the prediction that reduced
expression of the voltage-gated calcium channel subunit α2∂2 by overactive mTOR signaling in TSC leads to
dysregulated calcium homeostasis and aberrant hippocampal network activity. (1) At the molecular level, we
ask how α2∂2 expression is regulated by mTOR; (2) at the cellular level, we ask what is α2∂2’s role in dendritic
calcium signaling and glutamate receptor recycling in TSC deficient dendrites; and (3) at the network level, we
address the effect of α2∂2 in promoting aberrant hippocampal network activity. The proposed work is the first
to bridge the gap between underlying molecular/cellular mechanisms and hippocampal network
hyperexcitability in TSC, using a novel preclinical model to measure spike and seizure threshold for the first
time. The strength of our approach allows us to also test several interventions using our novel optogenetic
preclinical model of network activity. Notably, seizure medications do not target only the region of the brain that
seizures originate, but can reduce hyperexcitable neurons in other parts of the brain, such as the hippocampus
where ASD is tightly linked. Thus, we hypothesize that the hippocampus is vulnerable in children with TSC due
to neuronal and network hyperexcitabillity. These studies form the foundation for promising new therapeutic
strategies for TSC and other mTOR-related, complex brain disorders, with possible clinical applications.
Terms: <0-11 years old><Address><Ammon Horn><Autism><Autistic Disorder><Autoregulation><Behavior><Behavioral><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain region><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Calcium Ion Signaling><Calcium Signaling><Cell Communication and Signaling><Cell Signaling><Child><Child Youth><Children (0-21)><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Cornu Ammonis><Dendrites><Development><Disease><Disorder><Disturbance in cognition><Drugs><Early Infantile Autism><Encephalon><Encephalon Diseases><Epilepsy><Epileptic Seizures><Epileptics><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Foundations><Future><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glutamate Receptor><Hamartin><Health><Hippocampus><Hippocampus (Brain)><Homeostasis><Human><Impaired cognition><Individual><Infantile Autism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Ion Channel><Ionic Channels><Kanner's Syndrome><Kinases><Knowledge><Life><Link><Measures><Mechanistic Target of Rapamycin><Medication><Membrane Channels><Modern Man><Molecular><Mutation><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Organism><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Pre-Clinical Model><Preclinical Models><Protein Biosynthesis><RAFT1><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Rodent Model><Role><Seizure Disorder><Seizures><Signal Transduction><Signal Transduction Systems><Signaling><Synaptic plasticity><TSC1><TSC1 gene><Testing><Time><Transphosphorylases><Tuberous sclerosis protein complex><VDCC><Voltage-Dependent Calcium Channels><Work><autism spectrum disorder><autistic spectrum disorder><biological signal transduction><burden of disease><burden of illness><children><childrens'><clinical applicability><clinical application><cognitive dysfunction><cognitive loss><developmental><disability><disease burden><drug/agent><early childhood><epilepsia><epileptiform><epileptogenic><genome mutation><hippocampal><in vivo Model><interdisciplinary approach><interventional strategy><living system><mTOR><mammalian target of rapamycin><mouse model><multidisciplinary approach><murine model><network models><neurobiological><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic target><novel therapy approach><novel therapy target><optogenetics><protein synthesis><receptor recycling><response><social role><tuberous sclerosis complex><voltage><years of life lost to disability><years of life lost to disease><youngster>