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

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.

Genetic and neuroendocrine regulation of the postpartum brain

“…This finding is consistent with enrichment analysis within specific regions (Eisinger et al, 2013b, 2014; Driessen et al, 2014b; Zhao et al, 2014) and suggests that the maternal brain may represent a developmental endpoint in mammals. Structural changes in mothers across various regions (Leuner and Gould, 2010; Shams et al, 2012) suggests widespread CNS developmental and plasticity events occur in mothers.…”

“…In recent studies, we used high density microarrays that allowed for assessment of over 20,000 protein coding genes to assay gene expression changes in the postpartum CNS in four brain regions that contribute to the maternal phenotype: medial preoptic area (MPOA) (Driessen et al, 2014b), medial prefrontal cortex (mPFC) (Eisinger et al, 2014), lateral septum (LS) (Eisinger et al, 2013b), and nucleus accumbens (NAC) (Zhao et al, 2014). In these studies we compared the CNS of maternal to virgin mice and typically identified over 1000 genes per region with significant alterations in expression, suggesting a high level of change in the postpartum condition.…”

“…10, we identified 32 miRNAs that were reliably upregulated in maternal LS and 25 that were downregulated across multiple reproductive stages. We conducted that study because bioinformatics analysis of our microarray studies suggested a role for miRNAs in shaping gene expression (Zhao et al, 2012b; Driessen et al, 2014b; Eisinger et al, 2014). MiRNAs are small, non-coding RNAs that regulate gene expression by inhibiting RNA targets (Bartel, 2009).…”

Genetic mechanisms of parenting

“…Studies comparing wide-scale gene expression in postpartum and virgin rats, specifically in brain regions thought to be involved in parenting (e.g. MPOA, medial prefrontal cortex), support the notion that subsets of genes regulating maternal behavior and maternal memory are also implicated in psychopathologies like social disorders, depression, psychosis, and bipolar disorder Eisinger et al, 2014;Zhao et al, 2014). Thus the neural plasticity required during the normal shift to parenting also puts mothers at risk for mental health disorders often associated with the postpartum period.…”

Coexpression networks identify brain region–specific enhancer RNAs in the human brain

“…As a notable example, the rBEE at chromosome 6:21587723-21589288, which had a high M1 module membership (kME = 0.84; Online Methods), is located approximately 5 kb upstream of SOX4 and is most highly coexpressed with SOX4 and FABP7. SOX4 encodes a transcription factor important for neuronal differentiation 46 , and FABP7 has been recently implicated in ASD by gene expression studies, mutational analyses and mouse model studies [47][48][49] . In addition, the top 20 genes coexpressed with the rBEE at chromosome 6:21587723-21589288 also include AUTS2, which is associated with susceptibility to autism (Fig.…”