The Effects of Prenatal Iron Deficiency and Risperidone Treatment on the Rat Frontal Cortex:  A Proteomic Analysis

Abstract

Prenatal iron deficiency (pID) has been described to increase the risk for neurodevelopmental disorders such as autism and schizophrenia; however, the precise molecular mechanisms are still unknown. Here, we utilized high-throughput MS to examine the proteomic effects of pID in adulthood on the rat frontal cortex area (FCA). In addition, the FCA proteome was examined in adulthood following risperidone treatment in adolescence to see if these effects could be prevented. We identified 1501 proteins of which 100 were significantly differentially expressed in the FCA at postnatal day 90. Pathway analysis of proteins affected by pID revealed changes in metabolic processes, including the tricyclic acid cycle, mitochondrial dysfunction, and P13K/Akt signaling. Interestingly, most of these protein changes were not present in the adult pID offspring who received risperidone in adolescence. Considering the link between pID and several neurodevelopmental disorders such as autism and schizophrenia these presented results bring new perspectives to understand the role of iron in metabolic pathways and provide novel biomarkers for future studies of pID.

Ontogenetic oligodendrocyte maturation through gestational iron deprivation: The road not taken

“…Thus, the stellar subtype might be the cell type most likely to survive an insult than the other two OL subtypes. Recently, we have also found altered expression of proteins involved in metabolic processes including tricarboxylic acid (TCA) cycle and mitochondrial dysfunction in dID (Farrelly et al, ). These findings were associated with decreased expression of CNPase, PLP, MAG, MOG, and MBP, supporting the requirement of iron for optimal OL function and myelin synthesis.…”

“…C-WT, WT mice on a control diet; dID-WT, WT mice on an iron-deficient diet [Color figure can be viewed at wileyonlinelibrary.com] ID is one of the most important nutritional deficits, affecting almost 2 billion people worldwide. Maternal ID during gestation has been associated with important offspring neurological impairment, including motor and social neurological dysfunction (Bakoyiannis et al, 2015;Farrelly et al, 2017). When acquired during development, ID impacts OL maturation, which causes long-lasting hypomyelination in adulthood even after an iron-sufficient diet has been reinstated (Badaracco et al, 2008;Ortiz et al, 2004).…”

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation

“…Abnormalities in hippocampal energy metabolism have been documented in ID rats in adulthood, long after iron repletion (Carlson et al, 2007;de Deungria et al, 2000). Previous studies by our lab using labelfree liquid chromatography-tandem mass spectrometry (LC-MS/ MS) (Farrelly et al, 2017) et al, 2023). Most interestingly, given its location on the outer mitochondrial membrane, it has been speculated that DMT1 may participate in iron uptake in mitochondria.…”

“…Abnormalities in hippocampal energy metabolism have been documented in ID rats in adulthood, long after iron repletion (Carlson et al., 2007; de Deungria et al., 2000). Previous studies by our lab using label‐free liquid chromatography–tandem mass spectrometry (LC–MS/MS) (Farrelly et al., 2017) have demonstrated a pattern of dysregulated proteins involved in mitochondrial bioenergetics, the TCA cycle, and Akt signaling following prenatal ID. We have also recently demonstrated that ID OLG and AST obtained from a gestational ID model exhibit decreased spare respiratory capacity, which induces mitochondrial dysfunction.…”

Frontal Cortex Proteome Perturbation after Juvenile Rat Secondhand Smoke Exposure

“…Optimized methods provided good peak capacity with a 1D-LC method that was preferred over 2D-LC given the sample limitations working with the small orbital subdomain of the juvenile rat PFC, while still providing sufficient neuroproteome coverage. Across biological replicates, 2,067 proteins were identified from 20,504 reproducibly measured peptides in the OFC, which represented 38-66% greater neuroproteome coverage over recent proteomic studies in adult rat whole PFC or OFC [25–27] . Precisely 800 proteins (37.5%) were significantly responsive to juvenile ETS exposure at a 5% FDR (Table 1, Supporting Information), with 716 increased and 84 decreased (Figure 1A).…”