Patients with autism exhibit altered cognitive function that is revealed in EEG recordings as an imbalance of excitation to inhibition in the cerebral cortex. Imbalanced excitation / inhibition could be the product of multiple alterations of brain structure and function, such as an altered ratio of pyramidal neurons to interneurons in the autistic cerebral cortex. Imbalanced excitation / inhibition could also be produced by an alteration in the number of non-neuronal cell types (such as oligodendrocytes or astrocytes) that participate in neurotransmission;and / or by altered morphology or density of neuronal dendrites and dendritic spines in the cerebral cortex. Existing data on the relative number of specific cell types in the cerebral cortex of human autistic brains is at this point insufficient, as is data on the morphology of neurons in the human autistic cerebral cortex. The number of published studies is scarce, the number of cases included in the published studies is small, and the cases used for analysis is heterogeneous. A full understanding of the cellular basis of autism in human brain is essential for establishing the basic underlying mechanisms that, in turn, will result in therapeutic interventions. This project will analyze the temporal lobe of 21 autistic postmortem human brains (diagnosed as autistic, not as other autism spectrum disorders) and the temporal lobe of 18 control postmortem human brains, and investigate: 1) Density of total neurons, pyramidal neurons, and interneuronal subtypes in the autistic versus control temporal cortex using unbiased stereological methods for cell quantification. 2) Density of total glial cells, astrocytes, and oligodendrocytes in the autistic versus control temporal cortex using unbiased stereological methods. Cellular classification will be based on cellular morphology in Nissl stained sections, and on cellular marker expression in immunohistochemical experiments. 3) Dendrite length, dendritic branching, and spine density in the temporal lobe of autistic and control brains. We will stain neurons using the Golgi method, Neurolucida and the Scholl method to determine total dendritic length, total number of dendritic branches and spine density in pyramidal neurons and interneurons. We will classify our cases based on the subject's clinical history, including age, the presence of seizures or mental retardation, and the levels of social, communicative, and repetitive behaviors. We will statistically compare densities in the autistic versus control temporal cortex within clinical categories. A full understanding of the cellular basis of autism in the human brain is essential for establishing underlying mechanisms that in turn could yield new therapeutic interventions. The data obtained from this project will also serve as the basis for future studies focusing on the neuropathology and the imbalance excitation / inhibition of the autistic brain.

Public Health Relevance

Autism is a neurodevelopmental disorder defined by a pattern of qualitative abnormalities in reciprocal social interaction, communication, and repetitive interest and behavior. It is estimated that 1 in 110 children in the United States have autism spectrum disorders. The proposed project investigates the contribution of the density and morphology of distinct cortical cell types in the temporal lobe, to the pathogenesis of autism. A full understanding of the cellular basis of autism in the human brain is essential for establishing underlying mechanisms that in turn could yield new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094681-04
Application #
8660335
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gilotty, Lisa
Project Start
2011-06-02
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Rogers, Hailee; Ariza, Jeanelle; Monterrubio, Angela et al. (2016) Cerebellar Mild Iron Accumulation in a Subset of FMR1 Premutation Carriers with FXTAS. Cerebellum 15:641-4
Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth et al. (2016) Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals. Cereb Cortex 26:374-83
Hashemi, Ezzat; Ariza, Jeanelle; Rogers, Haille et al. (2016) The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Medial Prefrontal Cortex in Autism. Cereb Cortex :
Martínez-Cerdeño, Verónica (2016) Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models. Dev Neurobiol :
Martínez-Cerdeño, Verónica; Cunningham, Christopher L; Camacho, Jasmin et al. (2016) Evolutionary origin of Tbr2-expressing precursor cells and the subventricular zone in the developing cortex. J Comp Neurol 524:433-47
Hashemi, Ezzat; Ariza, Jeanelle; Lechpammer, Mirna et al. (2016) Abnormal white matter tracts resembling pencil fibers involving prefrontal cortex (Brodmann area 47) in autism: a case report. J Med Case Rep 10:237
Martínez-Cerdeño, Verónica; Noctor, Stephen C (2016) Cortical evolution 2015: Discussion of neural progenitor cell nomenclature. J Comp Neurol 524:704-9
Kim, Esther; Camacho, Jasmin; Combs, Zachary et al. (2015) Preliminary findings suggest the number and volume of supragranular and infragranular pyramidal neurons are similar in the anterior superior temporal area of control subjects and subjects with autism. Neurosci Lett 589:98-103
Ariza, Jeanelle; Steward, Craig; Rueckert, Flora et al. (2015) Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome. Brain Res 1598:88-96
Lozano, Reymundo; Martinez-Cerdeno, Veronica; Hagerman, Randi J (2015) Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder. Curr Pharm Des 21:4972-9

Showing the most recent 10 out of 19 publications