Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype.

Brian E. Eisinger,Stephen C. Gammie,Changjiu Zhao,Terri M. Driessen

doi:10.3389/fnbeh.2014.00110

Brian E. Eisinger, Stephen C. Gammie + Show 2 more

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https://doi.org/10.3389/fnbeh.2014.00110

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Abstract

The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia and BPD.

Highlights

The establishment of the maternal phenotype is one of the most dramatic biological transformations known in mature mammals
GENES WITH ALTERED EXPRESSION IN medial prefrontal cortex (mPFC) High density oligonucleotide microarray was performed on mPFC tissue collected from virgin and post-partum animals (Figure 1), and results were analyzed with the Probe Logarithmic Intensity Error (PLIER) algorithm
Genes of interest for quantitative real-time PCR confirmation were selected based on biological importance, statistical significance in the present microarray, and concordance with recent and ongoing expression studies in various other brain regions associated with maternal behavior

Summary

Introduction

The establishment of the maternal phenotype is one of the most dramatic biological transformations known in mature mammals. It involves changes across many physiological systems that prepare an individual to meet the demands of motherhood, including alterations within the brain that lead to the onset of adaptive parental and social behaviors (Lightman, 1992; Windle et al, 1997; Russell et al, 2001; Smith and Grove, 2002; Neumann, 2003; Slattery and Neumann, 2008; Levy et al, 2011). Motherhood carries a risk for post-partum depression, which affects 10–13% of new mothers. Recent experiments have begun to characterize large scale gene expression changes of lactating mice in various parts of this network, including septal regions and medial preoptic area (MPOA) (Zhao et al, 2012; Eisinger et al, 2013b; Driessen et al, 2014)

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