Anderson Laboratory Research Overview

Dysfunction of neocortical circuitry has been implicated in neuropsychiatric illnesses. While studies of mice and other animal models have led to tremendous advances in our understanding of how the brain develops, there are important species differences that are highly likely to impact how a neuropathological process affects cellular, circuitry, and brain function. In addition, the capacity to generate critical cortical neural subtypes could be invaluable for the discovery of therapeutic strategies based on cell replacement.

The Anderson Lab, and other labs, have spent many years understanding how cortical inhibitory interneurons, key mediators of the synchrony of cortical excitatory activity that underlies critical cortical functions, have their subtype fates determined during development.

In the Anderson Lab, we have successfully applied the field's incomplete knowledge of this process to generate key cortical interneuron subgroups from mouse embryonic stem cells (ESCs). In this project, we are applying our experience in mice to create efficient protocols for the generation of human cortical interneuron subgroups from human stem cells (ESCs and induced pluripotent stem cells). As these cells mature very slowly in the human brain, including major changes well into the adolescent age range, a critical component of this project includes the development of methods for accelerating the maturation of stem-cell derived neurons.

The major pathological manifestation of HIV-associated neurocognitive disorders in the antiretroviral treatment era is synaptodendritic damage. While significant strides have been made into understanding synaptodendritic damage, the current models are heavily restricted and there is no all-human in vitro model to help understand the basic mechanisms that lead to the observed damage.

Former graduate student Sean Ryan, PhD, now a postdoctoral fellow at Sanofi, developed a novel tri-culture model from human induced pluripotent stem cells to model interactions between neurons, astrocytes, and microglia during HIV infection. Overactive microglia leading to aberrant synaptophagocytosis has been implicated in multiple neurodegenerative and neurocognitive disorders including Alzheimer’s disease, multiple sclerosis, schizophrenia, and frontotemporal disorders.

In collaboration with the lab of Kelly Jordan-Sciuto, PhD, at Penn Dental Medicine, we are focusing on changes in inflammatory processes mainly by microglia and astrocytes, as well as changes in synaptophagy by HIV-infected microglia and/or uninfected, but activated, microglia.

In collaboration with Larry Singh, PhD, and Douglas Wallace, PhD, of the Center for Mitochondrial and Epigenomic Medicine at CHOP, and using whole-genome sequence data from the International 22q11.2 Brain and Behavior Consortium, the Anderson Lab is testing the hypothesis that, for people with 22q11.2 deletion syndrome, risk or resilience to developing schizophrenia will be affected by sequence variation in the mitochondrial-functioning nuclear and/or mitochondrial genome.

The Anderson Lab is studying the changes in mitochondria health and function in patients with 22q11.2 deletion syndrome and schizophrenia. Schizophrenia is a highly heterogeneous disease with a multitude of risk factors.

Patients with 22q11.2 deletion syndrome have a 25-fold rate increase in developing schizophrenia, and they are haploinsufficient for roughly 40 genes including six that are associated with mitochondria. Mitochondria deficits have been associated with schizophrenia, so we have utilized a rapid differentiation protocol to make a homogenous population of glutamatergic, neuron-like cells.

The Anderson Lab is studying the individual complex activities in mitochondria of these cells and have found significant deficits in several complexes as well as in overall ATP production compared to controls. We are continuing to study other mitochondria functions as well as overall neuronal functions, such as their electrophysiological properties. In the future, we will compare mitochondria function to patients with 22q11 deletion without schizophrenia.

Neonatal hypoxic ischemic encephalopathy (HIE) is estimated to occur in one to six per 1,000 births, with 25% of the affected children having significant neurodevelopmental disease. Variability of outcome in HIE may be secondary to numerous environmental factors, such as duration, degree and gestational timing of hypoxia, as well as placental abnormalities. There are likely to be additional genetic factors that predispose neonates with HIE to both hypoxic injury and poor neurodevelopmental outcome.

The Anderson Lab's central hypothesis is that the variable phenotypes seen in infants exposed to prenatal hypoxia are influenced by an individual’s capacity to withstand metabolic challenges, and more specifically, that neurodevelopmental abnormalities seen after hypoxic injury involve specific damage to and/or dysfunction of vulnerable developing interneurons via mitochondrial disruption.

The Anderson Lab is working with genetic mouse models of mitochondrial dysfunction in the setting of prenatal hypoxic injury using a variety of neurophysiology, cell biology, and behavioral techniques to characterize the interaction between hypoxic injury and mitochondrial dysfunction in interneurons.

In collaboration with the Laboratory of Ethan Goldberg, MD PhD, the Anderson Lab is attempting to treat and prevent epilepsy in experimental models of acquired focal epilepsy, as well as severe infantile-onset genetic epilepsies using progenitors of specific subtypes of cerebral cortical interneurons derived from embryonic stem cells.