Kloth, Alexander

• Postdoc., Neuroscience, University of North Carolina, Chapel Hill, NC 

• Ph.D., Molecular Biology and Neuroscience, Princeton University, Princeton, NJ 

• M.A., Molecular Biology, Princeton University, Princeton, NJ 

• Postbacc., Mental Health, National Institutes of Health, Bethesda, MD 

• B.S.E., Biomedical Engineering, Duke University, Durham, NC

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by socio-communicative deficits, repetitive behaviors, systemic interests, and other neurological and cognitive symptoms that have a wide range of severity. It is estimated that ~2.3% of children born today will receive an ASD diagnosis, with males estimated to be about three times as likely to receive an ASD diagnosis. Because of the high prevalence of ASD, decades of preclinical research have investigated the disorder's complex etiology and its manifestation in the brain, with the goal of uncovering effective therapeutic strategies. Despite these efforts, no treatments addressing ASD's core features have been successfully translated to the clinic.

A long-term goal of our laboratory is to determine whether treatments with neurotrophic actions-including environmental enrichment and pharmacological agents-might one day lead to successful therapies for ASD. One possible strategy that has recently attracted our attention involves erythropoietin (EPO) and its derivatives. EPO is an endogenous cytokine that has potent, long-lasting effects on cell survival, neuroplasticity, and neurogenesis, making it a candidate for treating a host of neuropsychiatric disorders, including ASD. However, EPO's potential has been limited by its severe hematological side effects. To overcome this hurdle, researchers have engineered non-hematopoietic derivatives that appear to have similar actions as EPO and appear to ameliorate disease features in model mice. For instance, we have recently shown that carbamoylated EPO (CEPO), which rescues anxiety and depression-related behavior in the BALB/c mouse model, also restores social approach behavior in these mice (Street et al., NeuroSci, 2025).

However, the degree to which CEPO rescues social and other ASD-related behaviors, the mechanisms underlying these potential behavioral changes, and the applicability of these findings to other ASD models all remain unclear.

The goal of the proposed project is to more broadly assess the effects of CEPO on ASD-related behaviors and examine the underlying neurobiological correlates of these effects. To do so, we will first employ a rigorously characterized idiopathic ASD mouse model, the BTBR T+Itpr3tfIJ (BTBR) mouse. BTBR mice show a broad suite of ASD-related behavior deficits and demonstrated decreased neurotrophic factor levels, diminished adult neurogenesis, aberrant neuronal morphology, and abnormal glial activity in the hippocampus, which are all potentially corrected by CEPO. We hypothesize the CEPO administration will rescue ASD-related social behaviors in BTBR mice in part by correcting these cellular and molecular defects. We will also examine the necessity of the endogenous erythropoietin receptor (EpoR), on which CEPO is thought to act, for ASD-related behaviors. We hypothesize that a conditional EpoR knockout will recapitulate the effects corrected in BTBR mice.

This project will provide undergraduate students to learn key skills in behavior, histology, immunohistochemistry, and molecular biology - all bedrock techniques in neuroscience - while exposing them to artificial intelligence, microscopy, and animal modeling techniques common in 21st century neuroscience.