Autism research has been a major strength at UCLA for decades, with the earliest work on effective treatments from Ivar Lovaas
performed here as well the first characterization of autism as a social communication disorder rather than a result of
dysfunctional maternal bonding, work spearheaded by Marian Sigman.
The autism imaging program has also grown substantially over the years. Current funded imaging projects include:
- An examination of the effects of autism risk polymorphisms on functional brain activity and connectivity (PI Bookheimer, Co-PI Geschwind)
- a Center grant project (PI McCracken) examining the effects of Risperidone on brain function in children with severe repetitive behaviors in the autism spectrum
- a Center grant project (PI Dapretto) examining mirror-neuron activity in high functioning children with autism and their relation to autism phenotypes
- a project (PI Woods) examining the effect of treatment for anxiety reduction on brain activation
- a center grant project evaluating brain differences in children with autism who received intensive behavioral treatment as toddlers
- a project examining the effects of restricted interests and social stimuli on reward-based learning and brain activity, in relation to the OXTR autism risk gene
The autism neuroimaging studies are interwoven with our autism genetics program directed by Dan Geschwind as well as a wide range of treatment programs,
from medication trials to social skills interventions to joint attention training.
Pat Levitt, newly appointed Director of the Zilkha Neurogenetic Institute (ZNI) and Chair of the Dept. Cell and Neurobiology at the Keck School of
Medicine at USC, has had long-standing scientific collaborations with IDDRC and neuroscience faculty at UCLA. This provides a unique opportunity for
the UCLA IDDRC to develop relevant collaborative ties with a sister institution in Los Angeles, adding strength to the translational research
initiatives that include the introduction of new core technologies.
Pat Levitt’s current collaborations include human genetic and developmental neurobiological studies with Dan Geschwind.
A new collaboration is established with Susan Bookheimer, examining the correlation of common genetic variants in risk genes that Levitt’s lab studies
with disrupted face and visual processing in children and adolescents with autism spectrum disorder.
Furthermore, Dr. Levitt brings to our IDDRC his clinical work in autism spectrum disorder with Children’s Hospital of Los Angeles (CHLA),
examining genetic and environmental factors that increase risk for autism spectrum disorder and co-occurring medical conditions (gastrointestinal conditions).
His recent publications reflect these translational research approaches that will benefit our IDDRC.
Pat Levitt’s leadership in the IDDRC network will be invaluable to the UCLA center, and he brings to our community newly recruited junior
faculty who will add strength to our translational research efforts.
Fragile X is a major cause of intellectual and developmental disabilities.
At UCLA, we have a working group devoted to research into this important neurodevelopmental syndrome. Work in Dr. Grody’s laboratory in Human Genetics is focusing on the genetic
testing of Fragile X in human patients
as well as the molecular underpinnings of this disease.
Dr. Silva and his group have been exploring the nature of the learning deficits in a mouse model of Fragile X.
Dr. Portera-Cailliau and his group have been using the same model to directly image the developmental time course of neuronal structural
abnormalities in the cortex using live imaging techniques.
Finally, Dr. Colwell and his group are developing interventions designed to stabilize the sleep and circadian deficits that are characteristic of Fragile X.
The hope is that by developing novel strategies to restoring sleep/wake cycles to these patients, it will be possible to improve quality of life for the
patients and actually improve cognitive performance.
Sleep and circadian disorders are common in IDD patients including those with autism and Fragile X and Rett diseases.
These disorders are extremely disruptive to both the patients and to those who provide care to the patients.
Furthermore, there is increasing evidence that sleep and circadian disorders can disrupt cognitive processes as well as increase the
likelihood of developing diabetes and heart disease. These observations raise the possibility that treating sleep and circadian disorders
will improve the general quality of life for IDD patients including cognitive performance.
A group of IDDRC faculty, including Drs. Block, Colwell, and Harper, is exploring the
interrelationships between IDD, sleep disorders, and cognitive performance.
Brain tumors are a significant cause of morbidity and mortality in children, with ill effects mediated by both the direct effects of the tumor as well as
the treatments—surgery, chemotherapy and radiation—required to eradicate the tumors or limit their growth. Novel, less toxic treatments for pediatric brain
tumors are urgently required.
Several laboratories, including the Kornblum lab working independently, but at approximately the same
time isolated cells from adult and pediatric brain tumor patients that have the characteristics of stem cells, in that they are extensively self-renewing,
and also are tumor initiating. These cells have been called “brain tumor stem cells” and have created a revolution in the study of brain tumors. These cells
are considered critical targets for the development of any potential therapies.
The Kornblum, Waschek and Sun labs are taking advantage of the availability of pediatric brain tumor specimens
for independent and collaborative work. The Kornblum laboratory is investigating critical genetic regulators of brain tumor stem cell growth in vitro
and in vivo. Additionally, they are performing high throughput screens as well as investigating candidate therapeutics d
eveloped by Industry and other academics to discover novel therapies. Furthermore, they are investigating mechanisms by which these brain tumor
stem cells resist current therapies. The Waschek laboratory has been studying the role of the hedgehog pathway and VIP-related peptides in medulloblastoma,
a common pediatric brain tumor, and has turned their attention to the study of these peptides and downstream signaling in murine and
human medulloblastoma stem cells. The Sun lab is collaborating intensively with the
Kornblum laboratory to uncover epigenetic mechanisms underlying brain tumor stem cell proliferation, by comparing cultures enriched and depleted for brain tumor stem cells.
Human pluripotent embryonic stem cells (hESCs) and human induced pluripotent stem cells (h-iPSCs) are beginning to revolutionize our way to approach functional
genomics, disease modeling, disease mechanistic study, drug screening, and development of novel therapeutic interventions. Particularly, with iPSC technology,
where patient-specific cells are utilized as research objects, there is the potential to develop population-wise stratified or even personalized
effective therapeutic medicine.
In the past few years, Dr. Sun's group has been working on hESC-based Rett syndrome modeling. This disease is a neural
developmental disorder and also an autism spectrum disorder (ASD), which is caused by loss-of-function genetic mutations of an X-chromosone-linked
methyl-CpG binding protein gene, MeCP2.
Dr Sun's group created MeCP2-deficient human ESC-derived neurons by using a shRNA knockdown approach via
lenti-viral mediated gene transfer. They found that MeCP2 deficiency led to a robust phenotype revealing the imbalance between excitatory and inhibitory
synaptic transmission, a phenotype that has been reported in MeCP2 knockout mice, as well as in ASD. Moreover, through extensive gene expression micro-array analysis,
her group identified a list of genes with altered expression due to MeCP2 deficiency, many of which are also reported to be linked to ASD. These genes could be
very strong candidates for novel drugable targets for RTT or other ASD. Additional gain and loss of function analyses are going on to test this hypothesis.
Meanwhile, Dr. Sun's group is currently making Rett syndrome iPSCs using patient-specific fibroblasts. Given that her lab in collaboration with other
labs in UCLA, have already created Huntington and Fragile-X iPSCs, as well as normal human iPSCs from a spectra of human somatic cells including fibroblasts,
keratinocytes, and apipose stem cells, amniotic fluid cells, they have the strong expertise in pushing the usage of this novel disease modeling technology
to the broader research community at UCLA IDDRC.
In addition, because of the strong epigenetic background, her group has the expertise to deal with the
heterogeneity created during the induction/ generation of iPSCs, which has emerged as a major obstacle in h-iPSC application.
The members of the Systems Neuroscience Group (Levine) study brain function from physiological, morphological, and behavioral standpoints during the course of development and
during learning in animal models and humans. Group members examine the mechanisms by which genetic, epigenetic, or brain injury or biological factors (e.g. infections)
affect the physiological, behavioral and cognitive functions of the nervous system and can cause or contribute to IDD. These studies often follow the developmental
trajectories of different brain functions and their influence on development of learning and cognition, communication and social behaviors. The faculties are Block,
Chesselet, Colwell, Hovda, Krantz, Levine, Maidment, Mathern, Martin, Silva, Phelps, White and Yang. Recent highlighted research activities of members of this group
that are sponsored and supported by the IDDRC include:
- Mathern, Levine and Cepeda have studied pediatric epilepsy and genetic disorders underlying it such as tuberous sclerosis (TSC) and brain malformations
such as cortical dysplasia.
These disorders cause severe IDD and common to these pathologies is the occurrence of seizures, cognitive deficits and high incidence of autism. They have described the morphological
and functional properties of normal and abnormal cell types and generated the dysmaturity hypothesis of epileptogenesis based on the presence of immature pyramidal neurons and high
GABA relative to glutamatergic synaptic activity, resembling the properties of immature brains and suggested GABAB receptor agonists could have therapeutic effects in severe cortical
dysplasia. In TSC they have shown that rapamycin, an immunosuppressant that negatively regulates the mTOR pathway, reduces neuronal excitability and has potential as a treatment for
epileptic seizures providing a new platform for translational studies in epilepsy and developmental disabilities.
- Silva’s studies using molecular and cellular mechanisms underlying the learning and memory deficits of transgenic mo
dels of IDD including TSC and neurofibromatosis type1 (NF1) revealed that
neurofibromin, the gene disrupted in NF1, regulates GABA release in the prefrontal cortex (PFC) and that this leads to the hypoactivation of PFC circuits and consequently working memory deficits.
Statins were shown to reverse these deficits. Studies with a TSC mouse model revealed that the learning and memory deficits of these mutants were caused by abnormal late
long-term potentiation
caused by changes in mTOR signaling and pointed to use of rapamycin therapies similar to findings described for the seizures.
- The roles of genes in memory and learning have been examined in Martin’s laboratory. They showed that synaptic stimulation induced changes in gene expression in the cell nucleus during
learning-related synaptic plasticity and that importins localize to synapses by activity-dependent binding to the cytoplasmic tail of the NR1 subunit of the NMDA receptor.
They also discovered that synapse formation alters populations of localized mRNAs in rodent hippocampal neurons and directly visualized translation of a localized mRNA during
learning-related neuronal plasticity.
- Yang’s studies of a mouse model that carries a CNS-specific deficiency of the striatonigral medium spiny neuron-enriched transcription factor, Zfp521 show postnatal
developmental onset of motor stereotypic behaviors resembling the motor stereotypies associated with autism spectrum disorders and is developing novel therapeutics to
ameliorate such behavior.
- White examines how FoxP molecules participate in the formation of vocal learning circuitry in birds and the ongoing process of sensorimotor learning and have
relevance to diseases like autism.
- Chesselet, Levine, Krantz and Maidment have used combined genetic, morphological, electrophysiological and behavioral studies of
development and function of the basal ganglia and associated neural
structures in mouse models of various neurodevelopmental and neurodegenerative disorders.
- Block and Colwell’s laboratories study the cellular basis of circadian rhythms and have shown that disrupting the circadian system leads to memory deficits raising the possibility
that sleep disorders in IDD patients may contribute to cognitive dysfunctions.
- Phelps examines spinal cord development in reeler mutant mice and demonstrated that Reelin is involved in neuronal migration and circuits that become
important in the perception of pain.