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Autism spectrum disorder (ASD) now affects 1 in 68 children in the United States. Disorders within this spectrum share hallmark deficits in verbal and nonverbal communication, repetitive behavior, and social interaction. The cause of ASD is still unknown. Even though hundreds of genetic abnormalities have been identified in ASD, these markers account for less than 1% of all ASD cases. Researchers continue to search for pathological markers common to all or most cases of ASD. The research presented in this dissertation used a novel combination of state-of-the-art methods to investigate brain pathology in ASD. Postmortem anterior cingulate cortex (ACC) from ASD and typically developing brain donors was obtained from 2 national brain banks. The ACC was chosen for study because of its documented role in influencing behaviors characteristically disrupted in ASD. An initial study revealed elevated glial fibrillary acidic protein (GFAP) in ACC white matter from ASD brain donors compared to typically developing control donors. Laser capture microdissection was then employed to isolate specific cell populations from the ACC from ASD and control brain donors. Captured cells were used to interrogate potential gene expression abnormalities that may underlie biological mechanisms that contribute behavioral abnormalities of ASD. The expression of 4 genes associated with synaptic function, NTRK2, GRM8, SLC1A1, and GRIP1, were found to be significantly lower in ACC pyramidal neurons from ASD donors when compared to control donors. These expression abnormalities were not observed in ACC glia. Given robust evidence of neuronal and glial pathology in the ACC in ASD, a novel method for whole transcriptome analysis in single cell populations was developed to permit an unbiased analysis of brain cellular pathology in ASD. A list of genes that were differentially expressed, comparing ASD to control donors, was produced for both white matter and pyramidal neuron samples. By examining the ASD brain at the level of its most basic component, the cell, methods were developed that should allow future research to identify common cellular-based pathology of the ASD brain. Such research will increase the likelihood of future development of novel pharmacotherapy for ASD patients.

The purpose of the present thesis was to propose a guideline to differentiate between an accidental or suicide manner of death when dealing with a drug/ethanol overdose in which all available medical and investigational evidence, including a psychological autopsy, is inconclusive, thereby resulting in an undetermined manner of death. An in-depth literature review was conducted in the field of neuroscience, psychiatry, and pharmacology to discover neuroanatomical markers indicative of suicidal behavior in the context of two major risk factors of suicide, stress and depression, and two hypotheses behind the cause of suicidal behavior, impulsive aggression and neuronal plasticity. The neuroanatomical markers of suicidal behavior, as indicated by the experimental evidence of various studies in suicide subjects, included serotonergic dysfunction, hypothalamic-pituitary-adrenal axis hyperactivity, brain-derived neurotrophic factor deficiency, and the associated anatomical changes in the brain. Upon consideration of the forensic applicability of analyzing these neuroanatomical markers indicative of suicidal behavior, a guideline was generated to differentiate between an accidental and suicide manner of death by showing suicide subjects had significantly decreased messenger ribonucleic acid and protein levels of presynaptic serotonin receptors along with significantly increased messenger ribonucleic acid and protein levels of postsynaptic serotonin receptors in the prefrontal cortex, significantly decreased serum brain-derived neurotrophic factor levels, and significantly decreased messenger ribonucleic acid and protein levels of brain-derived neurotrophic factor and tyrosine kinase B receptors in the prefrontal cortex and hippocampus when compared to the levels of both depressed non-suicidal individuals and healthy controls. Given the significant difference observed between suicide subjects and controls, these differences in neuroanatomical markers may play an important role in the pathophysiology of suicidal behavior and have the potential to be used in establishing the intention of an individual in an overdose death to distinguish between an accidental or suicidal manner of death.

Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of overactivity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC overactivity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ H]flunitrazepam to GABA receptors at three anatomically defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA receptor binding density was observed among all subjects. No significant differences in the amount of binding to GABA receptors were observed between control subjects (n = 21) and MDD subjects (n = 9) or depressed suicide victims (n = 17). These results demonstrate that GABA receptor binding in the LC measured with [ H]flunitrazepam is not altered in subjects with depressive illnesses.