What causes autism? In Autism New Jersey’s original webinar series, Rutgers researchers will break down the science in simple terms. To watch the recorded presentations, visit www.autismnj.org/article/the-complex-causes-of-autism-webinar-series
Questions? Call 800.4.AUTISM or visit www.autismnj.org
M. Chiara Manzini, PhD Associate Professor Neuroscience and Cell Biology Rutgers Robert Wood Johnson Medical School
Child Health Institute of New Jersey
LANGUAGE USED
- autistic person/child will be used for individuals with an autism spectrum disorder diagnosis
- male and female will be used for individuals with XY or XX chromosomal sex, respectively
- profound autism will be used for autistic people who are nonverbal/ minimally verbal, with moderate to severe intellectual disability, and need 24/7 supervision
- (scientific jargon) in parentheses
THE AUTISM SPECTRUM
Sex bias 4:1 Male:Female
(Rosen et al., J of Autism and Developmental Disorders, 2021)
WHY SHOULD WE LOOK AT GENES?
❑ 60-90% of identical (monozygotic) twins both have ASD ❑ Fraternal (dizygotic) twins have a much lower chance of both having ASD (3-30%)
Autism is highly genetic, but how is it inherited?
HALF OF OUR GENOME COMES FROM EACH PARENT
chromosome
Identical twins come from the same cell = same genome
HOW ARE GENETIC CONDITIONS INHERITED?
5%
2%
One genetic change
Multiple genetic changes
100%
10%
8%
Multiple genetic changes (polygenic) ➤ each adds some risk for the condition Type 2 diabetes, Polycystic ovary syndrome
One genetic change (monogenic) ➤ altering one gene is sufficient
Sickle cell disease, Duchenne muscular dystrophy
IS THERE ONLY ONE GENETIC CAUSE OR MANY?
The same gene or combination of genes lead to ASD
Many different genetic disruptions can lead to ASD
THE CHALLENGES
❑ Single-gene or multi-gene conditions are studied in different ways ❑ Single-gene: Collect DNA from autistic individuals and family members ❑ Multi-gene: Genome-wide association studies (GWAS) with DNA from large numbers of cases and controls
❑ ASD presentation is variable
❑ Severe ASD can be part of a more complex genetic syndrome (e.g. Fragile X Syndrome)
❑ Initial studies revealed that we need thousands of participants for either one
Large research groups
Studies
(de Sousa Nobrega et al., Int J Mol Sci, 2024)
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD
(Autism Science Foundation)
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD – SINGLE-GENE (FRAGILE X SYNDROME)
❑ Intellectual disability ❑ 20-30% are diagnosed with ASD ❑ Facial dysmorphism, epilepsy ❑ on the X chromosome – more severe in boys
❑ FMR1 regulates a large network of other genes
❑ Accounts for up to 1% of autistic individuals ❑ Inherited single gene variants account for 3-5% of ASD
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD – SINGLE NUCLEOTIDE VARIANTS (SNV)
de novo
(Fu et al, Nature Genetics, 2022)
WHAT IS A DE NOVO VARIANT?
❑ Only found in the autistic child on one chromosome (heterozygous) ❑ Originated in the sperm or egg of the parent
❑ De novo variants are preferentially inherited from older fathers ❑ Sperm is produced throughout life and is more susceptible to de novo changes with age
(Antaki et al, Nature Genetics, 2022)
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD – COPY NUMBER VARIANTS (CNV)
(Searles Quick et al., Neuropsychopharmacology, 2021)
WHAT ABOUT THE MULTI-GENE CAUSES?
(Autism Science Foundation)
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD – COMMON VARIANTS (MULTI-GENE)
❑ Each variant adds a little bit of risk
ASD RISK VARIANTS ADD UP
2%
5%
2%
90%
90%
8%
8%
3%
++
+++
+
ASD severity
CAN GENETICS EXPLAIN THE MALE BIAS?
❑ YES and NO ❑ Girls need more genetic risk variants to develop ASD
❑ Current rare single gene changes have same risk in males and females
(Koko et al, Am J Human Genetics, 2025; 21,501 ASD, 9,223 TD sibs)
(Antaki et al., Nature Genetics, 2022; 12,270 ASD, 5,190 TD sibs, 19,917 parents)
WHY ARE THERE SO MANY GENES?!
One third (15,000+) of 20,000+ human genes are active in the brain
Neuron
(Bekkers, 2011)
EACH NEURON
❑ Can receive more than 10,000 contacts (synapses)
Information collection
❑ There are 80 billion neurons in the human brain
❑ 800 trillion contacts/synapses
Response
THE NEURON’S GENES
The neuron’s genes control: ▪ Identity ▪ Location ▪ Response ▪ Plasticity
GENES MUTATED IN ASD
ASD risk genes control: ▪ neuronal communication, synapse function and plasticity ▪ synaptic proteins, ion channels ▪ expression of hundreds of other genes ▪ epigenetic regulators, transcription factors ▪ neuronal responses to nutrients and growth factors ▪ signaling proteins
ASD risk genes are involved in fetal development They are often only partially changed in their function
HOW DOES THIS HELP ME?
❑ Inherited and de novo monogenic cases can benefit from research on their specific gene ❑ rate of inheritance ❑ knowledge on how the condition progresses ❑ specialized therapies (gene therapy?) ❑ We can learn how to group genetic causes for better therapeutics
❑ Results on brain changes found in genetic cases can be applied to other autistic individuals
(Chahrour et al., J Neuroscience, 2016)
WHAT ARE WE STILL MISSING?
❑ Most genetic research has been done of people of European ancestry ❑ Asia, Africa, and Latin America may have non-overlapping genetic causes ❑ More recruitment is needed in both European and non-European populations for polygenic and ultra-rare variants ❑ Maternal genetics – maternal risk and changes in the function of the placenta during fetal development ❑ Gene X environment interactions ❑ More comparison of single-gene causes to find patterns
RESOURCES
❑ Simons Foundation – SFARI Gene https://gene.sfari.org/ ❑ Recurrence rates from ASF - https://autismsciencefoundation.org/quick-facts- about-autism/
❑ Current genetic study recruitment in NJ ❑ Simons Foundation for Autism Research – SPARK project recruitment at Children’s Specialized Hospital ❑ https://sparkforautism.org/csh ❑ sparkcsh@childrens-specialized.org ❑ “ SPARK is a privately funded research study on autism, meaning we receive no money from the government. Your privacy is very important to us.”
Goals for today
• Define “environment” and how it is measured • Describe mechanisms by which environment and genetics interact • Provide a few (not exhaustive) examples of gene x environment interactions in autism
Core and Associated Features
Rosen, Lord and Volkmar, 2022
Autism is Complex
Diagnosis or Dimension?
Increase in prevalence = Something in the environment?
Increase in prevalence = Correlation does not mean causation
First genes, now environment
Typically, they have been studied separately
Typically, they have been studied separately
They are not always independent things
Environmental effects may reflect genetic influences
How are they studied?
Direct assessment
Electronic Medical Records Monitoring station
Self Report
Environmental Factors on Autism Diagnosis
Exposure
Relative Risk/Odds Ration
Air Pollution during pregnancy
1.25-2x
Illness during pregnancy
2-3x 1.3x 4-5x
Maternal diabetes (blood sugar?)
Prematurity /very low birth weight/traumatic birth
Parental age
1.3 – 1.4x
Valproic acid (anti – seizure)
5x
Studied, no association
Exposure Plasticizers
Medical procedure/medicine
Terbutaline Fluoxetine
Maternal cigarette smoking
Maternal marijuana
IVF
Breast feeding
C-section Vaccines acetaminophen Tomiprimate (anti-seizure) antipsychotics
A model for both Causes
Genetics of mother and father
Gene/ Environment
Environment
HOW??
Genetics of fetus
Autism Phenotype
Which genome? Which environment?
Gardner et al., 2024
A model for both
Gene-Environment
Gene susceptibility or resilience
Gene transcription
DNA damage or repair
Overlapping targets
epigenetics
Immune
microbiome
Example of one influencing the other: Advanced Parental Age
Result of genetics?
Older Parents
Dehesh et al., 2024
Each color a different family
Diagnosis or Dimension? Vitamin D
Small effect in f only
Lower Vitamin D levels, higher ASD features Result of genetics?
Horsdal et al., 2025
NT overall male female
Aargard et al, 2024
Wyndham et al, 2020
Maternal Conditions
What is the link? Underlying gene or high blood sugar?
Gestational diabetes
Sibling analyses
Sibling – no diabetes but ASD dx
Beier et al., 2025
Guo et al., 2022
Folic Acid Protection
ENVIRONMENT THAT TARGETS THOSE GENES
GENETIC INFLUENCES-MTHFR677
Schmidt et al., 2012
Focusing on the antioxidant pathway
Folic Acid + pesticide exposure
Schmidt et al., 2017
Takeaways • Autism is not caused by one thing, even though scientists have been studying one thing at a time
• Many environmental associations may be attributed to genetic variations
• Beware of correlative studies
• You can’t study gene x environment interactions without understanding genetics – support newborn screening and genetic testing in ASD
Ultrasound
40
ASD
35
no ASD
30
Ultrasound by itself – diagnosis? – no difference
25
20
15
10
5
0
0
1
2
3
4
5
6+
Grether et al., 2010
Copy Number Variation
Copy Number Variants
5 x more likely to have an autism diagnosis if there is a CNV present • 100+ genes • Also seen in ADHD, Schizophrenia and IDD
Mollon et al., 2023
CNV + ultrasound on behavior
Domain
Effect
Social affect
11.4 vs. 11 – small diff 6.4 to 6.6 – small diff
Restricted and repetitive behaviors using observation
In those with CNVs and autism and ultrasound Dimensional not diagnostic
Noverbal IQ
87 vs 76 – larger diff
Social reciprocity RRB using parent report
No diff No diff
Webb et al., 2016
CNV + infection on autism features
Domain
Effect alone
Effect combined
Social communication
No changes with each alone No changes with each alone
Changes with both (16 to 18)
Social Interaction Increase scores with both (20 to 22) Nonverbal IQ Effect on CNV Same as CNV alone Social responsiveness Slight decrease with CNV Changes with both RRB using parent report and observation Slight decrease with CNV Changes with both
Mazina et al. 2015
Interaction – mechanism?
40
35
30
25
20
15
10
5
0
communication
social interaction
RRB
No CNV no MI
No CNV + MI
CNV no MI
CNV + MI
Mazina et al. 2015
References 1. Rosen, N. E., Lord, C., & Volkmar, F. R. (2021). The Diagnosis of Autism: From Kanner to DSM-III to DSM-5 and Beyond . Journal of Autism and Developmental Disorders , 51 (12), 4253 – 4270. https://doi.org/10.1007/s10803-021-04904-1
2. Gardner, R. M., Brynge, M., Sjöqvist, H., Dalman, C., & Karlsson, H. (2024). Maternal Immune Activation and Autism in Offspring: What Is the Evidence for Causation? Biological Psychiatry , S0006-3223(24)01760-8. https://doi.org/10.1016/j.biopsych.2024.11.009
3. Dehesh, T., Mosleh-Shirazi, M. A., Jafari, S., Abolhadi, E., & Dehesh, P. (2024). A assessment of the effects of parental age on the development of autism in children: A systematic review and a meta-analysis. BMC Psychology , 12(1), 685. https://doi.org/10.1186/s40359-024-02184-9
4. Windham, G. C., Pearl, M., Poon, V., Berger, K., Soriano, J. W., Eyles, D., Lyall, K., Kharrazi, M., & Croen, L. A. (2020). Maternal Vitamin D Levels During Pregnancy in Association With Autism Spectrum Disorders (ASD) or Intellectual Disability (ID) in Offspring; Exploring Non-linear Patterns and Demographic Sub-groups. Autism Research: Official Journal of the International Society for Autism Research , 13(12), 2216 – 2229. https://doi.org/10.1002/aur.2424
References 5. Aagaard, K., Møllegaard Jepsen, J. R., Sevelsted, A., Horner, D., Vinding, R., Rosenberg, J. B., Brustad, N., Eliasen, A., Mohammadzadeh, P., Følsgaard, N., Hernández-Lorca, M., Fagerlund, B., Glenthøj, B. Y., Rasmussen, M. A., Bilenberg, N., Stokholm, J., Bønnelykke, K., Ebdrup, B. H., & Chawes, B. (2024). High-dose vitamin D3 supplementation in pregnancy and risk of neurodevelopmental disorders in the children at age 10: A randomized clinical trial. The American Journal of Clinical Nutrition , 119(2), 362 – 370. https://doi.org/10.1016/j.ajcnut.2023.12.002 6. Horsdal, H. T., Albiñana, C., Zhu, Z., Boelt, S. G., Borbye-Lorenzen, N., Cohen, A. S., Skogstrand, K., Melgaard, L., MacSween, N. J., Thorbek, M. J., Plana-Ripoll, O., Petersen, L. V., Bulik, C. M., BRglum, A. D., Mors, O., Nordentoft, M., Werge, T., Moen, G.-H., D’Urso, S., … McGrath, J. J. (2025). Convergent evidence linking neonatal vitamin D status and risk of neurodevelopmental disorders: A Danish case-cohort study. The Lancet Psychiatry , 12(6), 410 – 420. https://doi.org/10.1016/S2215-0366(25)00099-9 7. Guo, D., Ju, R., Dai, J., & Zhang, H. (2025). Autism Spectrum Disorders in Offspring Exposed to Maternal Gestational Diabetes: A Meta-Analysis and Systematic Review. Review Journal of Autism and Developmental Disorders , 12(1), 69 – 79. https://doi.org/10.1007/s40489-023-00380-8 8. Khachadourian , V., Arildskov, E. S., Grove, J., O’Reilly, P. F., Buxbaum, J. D., Reichenberg, A., Sandin, S., Croen, L. A., Schendel, D., Hansen, S. N., & Janecka, M. (2025). Familial confounding in the associations between maternal health and autism. Nature Medicine , 31(3), 996 – 1007. https://doi.org/10.1038/s41591-024-03479-5
References 9. Hope, H., Pierce, M., Gabr, H., Radojčić, M. R., Swift, E., Taxiarchi, V. P., & Abel, K. M. (2024). The causal association between maternal depression, anxiety, and infection in pregnancy and neurodevelopmental disorders among 410 461 children: A population study using quasi-negative control cohorts and sibling analysis . Psychological Medicine , 54(8), 1693 – 1701. https://doi.org/10.1017/S0033291723003604 10. Beier, M. A., Setoguchi, S., Gerhard, T., Roy, J., Koffman, D., Mendhe, D., Madej, J., Strom, B. L., Blaser, M. J., & Horton, D. B. (2025). Early childhood antibiotics and chronic pediatric conditions: A retrospective cohort study. The Journal of Infectious Diseases , jiaf191. https://doi.org/10.1093/infdis/jiaf191 11. Schmidt, R. J., Tancredi, D. J., Ozonoff, S., Hansen, R. L., Hartiala, J., Allayee, H., Schmidt, L. C., Tassone, F., & Hertz-Picciotto, I. (2012). Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. The American Journal of Clinical Nutrition , 96(1), 80 – 89. https://doi.org/10.3945/ajcn.110.004416 12. Schmidt, R. J., Kogan, V., Shelton, J. F., Delwiche, L., Hansen, R. L., Ozonoff, S., Ma, C. C., McCanlies, E. C., Bennett, D. H., Hertz-Picciotto, I., Tancredi, D. J., & Volk, H. E. (2017). Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder. Environmental Health Perspectives , 125 (9), 097007. https://doi.org/10.1289/EHP604
References
13. Grether, J. K., Li, S. X., Yoshida, C. K., & Croen, L. A. (2010). Antenatal ultrasound and risk of autism spectrum disorders. Journal of Autism and Developmental Disorders , 40(2), 238 – 245. https://doi.org/10.1007/s10803-009-0859-4
14. Mollon, J., Almasy, L., Jacquemont, S., & Glahn, D. C. (2023). The contribution of copy number variants to psychiatric symptoms and cognitive ability. Molecular Psychiatry , 28(4), 1480 – 1493. https://doi.org/10.1038/s41380- 023-01978-4
15. Webb, S. J., Garrison, M. M., Bernier, R., McClintic, A. M., King, B. H., & Mourad, P. D. (2017). Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound. Autism Research: Official Journal of the International Society for Autism Research , 10(3), 472 – 484. https://doi.org/10.1002/aur.1690 16. Mazina, V., Gerdts, J., Trinh, S., Ankenman, K., Ward, T., Dennis, M. Y., Girirajan, S., Eichler, E. E., & Bernier, R. (2015). Epigenetics of autism-related impairment: Copy number variation and maternal infection. Journal of Developmental and Behavioral Pediatrics: JDBP , 36(2), 61 – 67. https://doi.org/10.1097/DBP.0000000000000126
Autism New Jersey | The Power of Connection
800.4.AUTISM | www.autismnj.org
The Complex Causes of Autism Webinar Brain Developmental Causes
Emanuel DiCicco-Bloom, MD Neuroscience and Cell Biology/Pediatrics Rutgers Robert Wood Johnson Medical School
May 22, 2025
New Jersey Autism Center of Excellence RUCARES
Rutgers, The State University of New Jersey
Neurodevelopmental Disorders What does that mean?
- Autism Spectrum Disorder (ASD)
- Developmental Delay
- Intellectual Disability
- Learning Disability
- Attention Deficit Hyperactivity Disorder
- Specific Language Impairment
- Tourette’s Syndrome
- Schizophrenia
- Bipolar Depression
What are the symptoms of ASD?
Problems with eye contact
No response to one’s name
Problems following another person’s gaze or pointing, “joint attention”
Reduced facial expression that does not match what is being said, or the expression’s of others
Excessive lining up of toys
Abnormally intense or focused interest
Preoccupation with moving objects, or parts of objects (truck wheels!)
Repetitive hand or arm movements (flapping)
Inflexible adherence to specific routines or rituals (nighttime)
Unusual language – few spontaneous words, echolalia
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
Hallmark Feature - Abnormal Social Interaction
RT Schultz et al, 2000
How Common is ASD?
Prevalence of ASD is 1:31 nationwide (3.22%)
40.4% with intellectual disability among boys
More common in males than females (3.4:1 ratio)
Ratio varies by cause
www.cdc.gov/
Autism Spectrum Disorders (ASD)- DSM-5 Diagnostic Criteria A. Persistent deficits in social communication and social interaction across multiple contexts B. Restricted, repetitive patterns of behavior, interests, or activities C. Present in early developmental period (Recognized 12 – 24 months) D. Significant impairment in social, occupational, or other functioning E. Not better explained by intellectual disability or global delay
Specifiers:
+/- intellectual impairment +/- language impairment +/- genetic, medical, environmental factor-FXS, Tuberous Sclerosis, Rett, Epilepsy, Valproic acid (Depakene), Very Low Birth Weight
Co-Morbidity: 70% with one another disorder, and 40% with two! Anxiety & Mood(>60%), Epilepsy (30%), ID (65%), ADHD, OCD
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
Autism Spectrum Disorder has a Genetic Basis
GENES
ENVIRONMENT
Twin Studies 61-94% concordance rate among identical/monozygotic twins
10-17% concordance rate among dizygotic/fraternal twins
Family Studies Risk of developing autism is 10 times greater for siblings of autistic individuals than for general population, occurring 10-20% We consider the non-genetic factors to be in part environmental, that is the intrauterine environment: Medications (Valproic acid), maternal infection, challenging delivery, very low birth weight; may be differences in placental function, maternal stress, chemicals like pesticides
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
CEREBRAL CORTEX
Parietal Cortex sensation association
Frontal Cortex planning language motor Temporal Cortex Hippocampus Amygdala social emotion fear
Occipital Cortex vision
CEREBELLUM movement cognition
learning/memory neurogenesis
Autism : Smaller cerebellar vermis Lost Purkinje neurons
Cerebral Cortex Neurons in Culture
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
The Synapse
Genetic changes of the
synapse cause multiple
neuropsychiatric disorders
of development
Stages of Brain Growth
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
Stages in Neuron Production
Noctor & Kriegstein
Neurite
Cell body
Cell proliferation
Process/Neurite growth
Migration
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
There is No Consistent Abnormality in ASD Postmortem Brains: All of the following differences have been seen: Brain Size ASD & Abnormal Brain Development
• 20% Macrocephaly (Bigger brains) • 10% Microcephaly (Smaller brains)
Proliferation
Location of Neurons -Incorrect positioning -Disrupted layers Neuron Abnormalities -Too many or too few neurites -Synapse number
Migration
Differentiation
-Abnormalities in neurotransmitters -Electrophysiological abnormalities DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
The Synapse
Genetic changes of the
synapse cause multiple
neuropsychiatric disorders
of development
Genetic changes of the synapse cause multiple neuropsychiatric disorders of development
Fragile X Syndrome mutation leads to enhanced Glutamate signaling
FMR-KO+ mGluR5 Het
FMR-KO
mGluR5 Het
Wild Type
Mushroom
Stalk
Glutamate mGluR5 receptor antagonism reverses the FMR1 disease
FXS accounts for ~1% of ASD
40% of those with FXS have ASD
G Dolen, M Bear, 2007
Signs of Tuberous Sclerosis – Neurocutaneous Disorder- Epiderm
Angiofibroma “bumps”
Hypopigmented patches
Tubers
NT
ASD
Nodules
Tang et al, http://dx.doi.org/10.1016/j.neuron.2014.07.040
Peters et al, Future Neurol. 2013 8(5):583-597
During development from the fetus to adulthood, neuron and synapse numbers are in part regulated by pruning!
Microglia are the ‘Gardeners’ of the Brain!
Penna et al, Cerebral Cortex Communications, 2021, 2, 1 – 14
Functional MRI studies in typical and autistic individuals
Attention task
Typical
Autism
Motor task
Autism
Typical
Allen and Courchesne, 2003
Axon Bundles = White Matter tracts Neurites → Axons and Dendrites What Does it All Mean?
Shu et al 2001 Alexander et al 2007
What about the connections between neurons and brain regions?
We can use Functional MRI (fMRI) to measure connectivity
Local hyperconnectivity?
Long distance hypoconnectivity?
Savant abilities?
Delays in social and communication functions?
Frontal
Occipital
Due et al, DOI 10.3389/fnagi.2023.1101879
Recent Advances in ASD Diagnosis
Early structural and functional brain imaging accurately predicts ASD diagnosis at 24 months! Nature. 2017 Feb 15;542(7641):348-351 Structural brain MRI at 6 (Blue) and 12 (Red) months accurately predicts (81%) which children will be diagnosed with ASD at 24 mo, especially social deficits. Early expansion of the cerebral cortex. In families with one child with autism, the next born sibling has a greater chance of autism – Established the Baby Siblings Study = higher risk of ASD
Functional connectivity MRI at 6 months accurately predicts which children will be diagnosed with ASD at 24 months. Sensitivity, 82%; Specificity, 100%. Red (-), Blue (+) connectivity
Sci Transl Med. 2017 Jun 7;9(393). pii: eaag2882.
THERE ARE MANY DIFFERENT GENETIC CAUSES OF ASD
(Autism Science Foundation)
Satterstrom et al, 102 Genes - Categories
Hypo- and Hyper-connectivity can be defined in mouse genetic models – Why Mice?
Hypo-connectivity in BLUE
Does hypoconnectivity cause delays in social and motor behaviors?
Hyper-connectivity in RED
Pagani et al, https://doi.org/10.1101/2025.03.04.641400
This gene-connectivity relationship is now being applied to people
Social behavior in mice – preference for another mouse Engrailed-2 mutants do not prefer another mouse!
The Role of Oxytocin in Social Behavior Select Neuronal Circuits?
Social Behavior in Voles - Monogamous vs Non-monogamous
The neuropeptide oxytocin (OT) regulates social behavior, including pair bonding and maternal-infant relations. OT acts via OT-Receptor and Arg-Vasopressin 1a-R.
Monogamous Prairie Vole
Non-Monogamous Montane Vole
Highly social Communal burrows Biparental child care 80% mate for life Separation-ultrasonic distress Not aggressive to intruders Isolated burrows No paternal child care Mate with multiple partners Separation-little distress Human clinical trials? Failed. But clinical subgroups? Yes DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
Our Approach
16p11.2 Deletion CNV
NJLAGS idiopathic ASD dataset
Deletes 28 genes
Genetically undefined
Goal: Use iPSC-derived neuronal precursor cells (NPCs) to study the developmental and signaling pathways that are abnormal in these individuals
DiCicco-Bloom, Rutgers Robert Wood Johnson Medical School
Connacher R et al., Stem Cell Reports. 2022 May 17;S2213-6711(22)00208-9
Stages in Neuron Production
Noctor & Kriegstein
Neurite
Cell body
Cell proliferation
Process/Neurite growth
Migration
Family-1: Different rates of proliferation
DAY 2
DAY 4
DAY 6
Connacher R et al., Stem Cell Reports. 2022 May 17;S2213-6711(22)00208-9
Idiopathic ASD Neuronal Processes
Smrithi Prem
Prem S et al., eLife, 2024;13:e82809
Idiopathic ASD Neuronal Migration
Smrithi Prem
Prem S et al., eLife, 2024;13:e82809
Autism genetic and environmental factors act during gestation and affect neural precursor cell proliferation, migration, and process outgrowth
The gut microbiome and brain have heightened sensitivity to environmental factors during early life Do Genes interact with Environmental factors to impact brain development?
CDC estimates that an infant will receive 2-3 courses of antibiotics Susceptible to infections
Immune Vagus nerve Endocrine Metabolites
Aversa et al., (2021) Slykerman et al., (2019) Lavebratt et al., (2019) Wimberley et al., (2018)
Postnatal antibiotic exposure
Antibiotic-induced perturbations
Courtney R. McDermott, PhD Columbia University
Aversa et al., (2021) Slykerman et al., (2019) Lavebratt et al., (2019) Wimberley et al., (2018)
Chung et al., (2021) Niarchou et al., (2019) Duyzend & Eichler et al., (2015) Blumenthal et al., (2014)
Postnatal antibiotic exposure
16p11.2 microdeletion copy number variation
Association with NDDs
Warrants investigation of underlying biological mechanisms
Accounts for ~1% ASD cases
Early life treatment with antibiotic altered the gut microbiome, brain development, and behavior, and these effects were magnified in mice that were carrying the 16p11.2 CNV
McDermott et al., bioRxiv: https://doi.org/10.1101/2025.02.25.639888
Acknowledgments:
Robert Wood Johnson Medical School
Rutgers University
DiCicco-Bloom lab Smrithi Prem Robert Connacher Madeline Williams Xiaofeng Zhou Courtney McDermott Cynthia Peng Bharati Dev Anna Markov
Linda M. Brzustowicz Judy Flax
Jinchuan Xing Rohan Alibutud
Child Health Institute Che Wei Lu
Percy L Yeung Zhiping Pang
Center for Advanced Biotechnology and Medicine
Nancy Lurie Marks Family Foundation NIMH
James H. Millonig Monal Mehta Paul Matteson
Lurie Family Foundation Autism Research Institute Simons Foundation RUCDR New Jersey Governor ’ s Council for Autism Research Mindworks Charitable Lead Trust Jewish Community Foundation of Greater MetroWest NJ The Families!
Questions? Call 800.4.AUTISM or visit www.autismnj.org
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