Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders

Figure 1. Mechanisms involved in the development of the ASD-like phenotype in PZD mice. (A) Acute zinc deficiency during pregnancy profoundly affects brain and intestinal organogenesis of the developing offspring, ultimately leading to direct effects on the brain and indirect effects through gut-brain interaction. The underlying mechanisms are as follows: (B) Zinc deficiency alters the expression and function of proteins critical for tight junction formation and activates immune signaling mediated by NFkB. As a consequence, intestinal barrier tightness is compromised and bacterial components can enter the circulation, thereby producing an immune response. This process fuels the already activated NFkB-driven pro-inflammatory signaling establishing a chronic inflammation. Leaky gut and inflammation create a host environment that is more suitable for specific bacteria, thus shifting microbiota composition significantly. Through released factors and/or bacterial components directly, the development of the brain is modified. (C) Additionally, zinc deficiency has direct effects on the brain, most notably on synaptogenesis and function. Zinc deficiency impairs SHANK dependent PSD scaffold…

Figure 2. Associations between risk factors for autism. Evidence is mounting that several risk factors for ASD, such as maternal diabetes, prenatal stress, the use of certain drugs, the presence of toxic metals, and prenatal infection, all previously considered independent factors, converge on abnormal zinc signaling on biological level. Abnormal zinc signaling affects the development of the brain and GI system, and likely, other organ systems. Notably, zinc signaling is key to processes defined by genetic factors linked to ASD. Thus, abnormal zinc signaling is able to trigger and modify ASD pathology caused by a variety of genetic factors.

Figure 3. Prevention and treatment approaches based on data from PZD mice. Balancing trace metal levels, especially preventing zinc deficiency during pregnancy may be a promising prevention strategy. However, the bioavailability of zinc needs to be considered that can be impacted by folic acid supplementation and mineral supplements with high levels of Fe, Ca, and Cu. The exposure to toxic metals needs to be considered. Given that maternal infection and maternal diabetes are tightly linked to trace metal alterations, if infection or diabetes occurs, zinc supplementation may be an important preventive approach. In contrast, zinc supplementation may have a limited effect on patients with ASD after the critical time window of brain development in utero. Nevertheless, influencing zinc signaling locally in the brain and synapses may be a promising target for drug development. To that end, new zinc delivering compounds (zinc amino-acid conjugates, zinc ionophores, etc.) and nanoparticles, and drugs targeting proteins (MTs (metallothioneins), zinc transporters) regulating zinc homeostasis can be developed. Balancing alterations in the microbiome needs to be explored in terms of the effects on…