Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders

Abstract

Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex pathology emerges, with alterations in the gastrointestinal and immune system and synaptic signaling in the brain, as a major consequence of prenatal zinc deficiency. The features represent a critical link in a causal chain that leads to various neuronal dysfunctions and behavioral phenotypes observed in prenatal zinc deficient (PZD) mice and probably other mouse models for ASD. Given that the complete phenotype of PZD mice may be key to understanding how non-genetic factors can modify the clinical features and severity of autistic patients and explain the observed heterogeneity, here, we summarize published data on PZD mice. We critically review the emerging evidence that prenatal zinc deficiency is at the core of several environmental risk factors associated with ASD, being mechanistically linked to ASD-associated genetic factors. In addition, we highlight future directions and outstanding questions, including potential symptomatic, disease-modifying, and preventive treatment strategies.

Keywords: ASD; MIA; Shank3; autism; biometals; copper; mouse models; synaptopathy; trace metals.

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 formation, thereby affecting pre-synaptic function through trans-synaptic signaling via Neuroligin and Neurexin, which significantly affects synaptic vesicle function and trafficking by altering key proteins involved in the process such AKAP5. Abnormal vesicle release together with postsynaptic effects of abnormal SHANK physiology will alter neurotransmitter receptor signaling and ultimately affect important ASD-associated pathways such as mTOR signaling.

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 zinc availability. Finally, chronic inflammation resulting from the GI pathology linked to zinc deficiency could be addressed as early as possible as an intervention in ASD.