Author
Adam J. Funk
Other affiliations: University of Cincinnati Academic Health Center, University of Alabama at Birmingham, University of Cincinnati
Bio: Adam J. Funk is an academic researcher from University of Toledo. The author has contributed to research in topics: Dorsolateral prefrontal cortex & Prefrontal cortex. The author has an hindex of 12, co-authored 22 publications receiving 1606 citations. Previous affiliations of Adam J. Funk include University of Cincinnati Academic Health Center & University of Alabama at Birmingham.
Papers
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TL;DR: An epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect is highlighted.
1,176 citations
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TL;DR: Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3′–5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia.
129 citations
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TL;DR: There is an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia, which is suggested to contribute to the pathophysiology of schizophrenia.
86 citations
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TL;DR: The data suggest that NMDA receptor complex formation, localization, and downstream signaling may be abnormal in schizophrenia.
Abstract: Converging evidence suggests too few activation-ready N-methyl-D-aspartic acid (NMDA) receptor complexes in the postsynaptic density in schizophrenia. Postsynaptic density protein 95 (PSD95), Synaptic GTPase-activating protein (SynGAP), and Multiple PDZ domain protein (MUPP1) are integral components of the NMDA receptor signaling complex, and help facilitate signaling, trafficking, and stabilization. We hypothesized that deficits involving these molecules may contribute to the pathophysiology of schizophrenia. To test our hypothesis, we measured protein expression of PSD95, SynGAP, and MUPP1 in the anterior cingulate cortex and dorsolateral prefrontal cortex. We found decreased PSD95 expression in the anterior cingulate cortex. Antipsychotic medication analyses showed decreased SynGAP expression in the anterior cingulate cortex in patients off medication when analyzed against our comparison group. These data suggest that NMDA receptor complex formation, localization, and downstream signaling may be abnormal in schizophrenia.
82 citations
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12 Sep 2017
TL;DR: The data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia.
Abstract: Schizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia. A study by US scientists indicates that changes in the activity of key signaling proteins may underlie core symptoms of schizophrenia. Protein kinases mediate the activation of intracellular signaling events and analyses of the kinome, the complete set of protein kinases encoded in the genome, previously revealed significant changes in phosphorylation patterns in postmortem brain tissue from patients with schizophrenia. Based on these findings, Jennifer McGuire at the University of Cincinnati and colleagues investigated the upstream regulation of these proteins. They identified both established and novel proteins associated with schizophrenia in the anterior cingulate cortex, with JNK and AKT activity being the most disrupted in schizophrenia patients. Their findings highlight how subtle changes in the activity of a small number of signaling proteins can propagate and have major consequences for mental health.
52 citations
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TL;DR: An ecobiodevelopmental framework is presented that suggests that many adult diseases should be viewed as developmental disorders that begin early in life and that persistent health disparities associated with poverty, discrimination, or maltreatment could be reduced by the alleviation of toxic stress in childhood.
Abstract: in fields of inquiry as diverse as neuroscience, molecular biology, genomics, developmental psychology, epidemiology, sociology, and economics are catalyzing an important paradigm shift in our un- derstanding of health and disease across the lifespan. This converging, multidisciplinary science of human development has profound impli- cations for our ability to enhance the life prospects of children and to strengthen the social and economic fabric of society. Drawing on these multiple streams of investigation, this report presents an ecobiodeve- lopmental framework that illustrates how early experiences and envi- ronmental influences can leave a lasting signature on the genetic predispositions that affect emerging brain architecture and long-term health. The report also examines extensive evidence of the disruptive impacts of toxic stress, offering intriguing insights into causal mech- anisms that link early adversity to later impairments in learning, be- havior, and both physical and mental well-being. The implications of this framework for the practice of medicine, in general, and pediatrics, specifically, are potentially transformational. They suggest that many adultdiseasesshouldbeviewedasdevelopmentaldisordersthatbegin early in life and that persistent health disparities associated with pov- erty, discrimination, or maltreatment could be reduced by the allevi- ation of toxic stress in childhood. An ecobiodevelopmental framework alsounderscoresthe needfornewthinking aboutthe focus andbound- aries of pediatric practice. It calls for pediatricians to serve as both front-line guardians of healthy child development and strategically po- sitioned, community leaders to inform new science-based strategies that build strong foundations for educational achievement, economic productivity, responsible citizenship, and lifelong health. Pediatrics
3,248 citations
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TL;DR: Improved recognition and understanding of clinical, psychological, sociological, and biological factors might help the detection of high-risk individuals and assist in treatment selection.
1,254 citations
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TL;DR: These findings provide a unique opportunity for understanding how environmental factors can lead to individual differences in brain development, and for improving the programmes and policies that are designed to alleviate SES-related disparities in mental health and academic achievement.
Abstract: Socioeconomic status (SES) influences brain development. Farah and colleagues discuss evidence that prenatal factors, parent–child interactions and cognitive stimulation mediate this effect, and consider implications for alleviating SES-related disparities in mental health and academic achievement. Human brain development occurs within a socioeconomic context and childhood socioeconomic status (SES) influences neural development — particularly of the systems that subserve language and executive function. Research in humans and in animal models has implicated prenatal factors, parent–child interactions and cognitive stimulation in the home environment in the effects of SES on neural development. These findings provide a unique opportunity for understanding how environmental factors can lead to individual differences in brain development, and for improving the programmes and policies that are designed to alleviate SES-related disparities in mental health and academic achievement.
1,082 citations
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TL;DR: This review focuses on the enduring effects of naturally occurring variations in maternal care on gene expression and phenotype to provide an example of environmentally driven plasticity at the level of the DNA, revealing the interdependence of gene and environmental in the regulation of phenotype.
Abstract: Variations in phenotype reflect the influence of environmental conditions during development on cellular functions, including that of the genome. The recent integration of epigenetics into developmental psychobiology illustrates the processes by which environmental conditions in early life structurally alter DNA, providing a physical basis for the influence of the perinatal environmental signals on phenotype over the life of the individual. This review focuses on the enduring effects of naturally occurring variations in maternal care on gene expression and phenotype to provide an example of environmentally driven plasticity at the level of the DNA, revealing the interdependence of gene and environmental in the regulation of phenotype.
1,048 citations
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TL;DR: Using olfactory molecular specificity, the inheritance of parental traumatic exposure is examined and a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels is provided.
Abstract: Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor ( Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.
1,001 citations