Document text
Principal Investigator: Robert Desimone
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $225,900
Funding agency: National Institute of Mental Health
PROJECT SUMMARY/ABSTRACT
The ability to genetically modify the mouse genome has revolutionized biomedical research. However,
its impact on our understanding of brain disorders is limited partially due to the inherent differences in the
structure and physiology of the brain between rodents and humans. Most notably, the prefrontal cortex is one
of the largest and most developed portions of the human brain and a top candidate for pathological processes
in many psychiatric disorders. Yet, rodents have only a rudimentary prefrontal cortex and are thus limited in
exhibiting the complex cognitive functions that are mediated by this region. The lack of predictive animal
models is now considered one of the key bottlenecks in developing effective treatments for brain disorders.
Non-human primates are much more closely related to humans than are rodents, and this is reflected in
their brain development, structure and physiology. Hence, it is increasingly recognized that they provide an
attractive model to study higher brain function and brain disorders. The recent development of highly efficient
CRISPR genome-editing technology made it feasible to directly manipulate the genome in zygotes, thus
expanding genetic manipulations to many species including non-human primates.
In the past 4 years, we have been collaborating with a team of scientists in the Brain Cognition and
Brain Disease Institute, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences to
use CRISPR/Cas9 to generate macaque monkey models of monogenic ASD. We have now successfully
generated Shank3 mutant cynomolgus macaques. Shank3 is a glutamatergic postsynaptic scaffolding protein
critical for synapse development and function. Heterozygous mutations of the Shank3 gene in humans lead to
Phelan-McDermid syndrome (PMS), an autism spectrum disorder. Initial characterization of the 5 founder
Shank3 mutant monkeys revealed sleep disturbances, motor deficits, and increased repetitive behaviors, as
well as social and learning impairments. Unbiased analysis of fMRI data showed altered local and global
connectivity patterns indicative of circuit abnormalities. Together, these results parallel some aspects of the
gene-circuit-behavior dysfunction in human ASD and PMS. Here we propose, in collaboration with our
colleagues in SIAT, China, to generate F1 generation of Shank3 mutant monkeys to validate initial
observations, to further behavioral and neurophysiological characterization and to bring mutant sperms to US
for establishing a colony for sharing with autism research community.
Terms: <22q13 deletion syndrome><ASD><Academy><Animal Model><Animal Models and Related Studies><Animals><Autism><Autistic Disorder><Behavior><Behavioral><Biochemical><Biological Markers><Biomedical Research><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><California><Cas nuclease technology><China><Chinese><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cognition><Collaborations><Communities><Complex><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Development><Dysfunction><EEG><Early Infantile Autism><Electroencephalogram><Electroencephalography><Electrons><Encephalon><Encephalon Diseases><Exhibits><Fertilized Egg><Fertilized Ovum><Functional MRI><Functional Magnetic Resonance Imaging><Functional disorder><Future><Gene Alteration><Gene Modified><Gene Mutation><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genome><Germ Lines><Glutamates><Heterozygote><Human><Immediate Memory><Impairment><Infantile Autism><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Kanner's Syndrome><L-Glutamate><Lead><Learning><Light><M fascicularis><M mulatta><M. fascicularis><M. mulatta><Macaca><Macaca fascicularis><Macaca mulatta><Macaque><Mainland China><Mediating><Mental disorders><Mental health disorders><Microscopic><Modeling><Modern Man><Monkeys><Mutation><Negative Beta Particle><Negatrons><Neurobiology><Neurosciences Research><Pathologic Processes><Pathological Processes><Patients><Pattern><Pb element><Phelan-McDermid syndrome><Photoradiation><Physiology><Physiopathology><Prefrontal Cortex><Primates><Primates Mammals><Psychiatric Disease><Psychiatric Disorder><Research><Rest><Rhesus Macaque><Rhesus Monkey><Rodent><Rodentia><Rodents Mammals><Scaffolding Protein><Science><Scientist><Sequence Alteration><Short-Term Memory><Shortterm Memory><Sleep disturbances><Sperm><Sperm Transport><Spermatozoa><Structure><Study models><Synapses><Synaptic><Synaptic Potentials><Technology><Testing><aberrant sleep><autism model><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><behavior test><behavioral test><bio-markers><biologic marker><biomarker><cognitive function><cohort><developmental><disrupted sleep><disturbed sleep><effective therapy><effective treatment><fMRI><gene manipulation><gene modification><genetic manipulation><genetically manipulate><genetically modified><genetically perturb><genome editing><genome mutation><genomic alteration><genomic editing><glutamatergic><heavy metal Pb><heavy metal lead><heterozygosity><impaired sleep><irregular sleep><mental illness><model of animal><model of autism spectrum disorder><motor deficit><mouse genome><mutant><neural imaging><neuro-imaging><neurobiological><neurobiological mechanism><neuroimaging><neurological imaging><neuropathologic><neuropathological><neuropathology><neurophysiological><neurophysiology><non-human primate><nonhuman primate><pathophysiology><postsynaptic><psychiatric illness><psychological disorder><repetitive behavior><sleep disruption><sleep dysregulation><social><social cognition><social reciprocity><sperm cell><synapse><therapeutic target><therapeutically effective><working memory><zoosperm><zygote>