The effects of prenatal H1N1 infection at E16 on FMRP, glutamate, GABA, and reelin signaling systems in developing murine cerebellum
Prenatal viral infection may lead to disturbances in key signaling systems associated with brain development. In autism, schizophrenia, and mood disorders, there is ample evidence of dysfunction of multiple signaling systems including gamma‐aminobutyric acid (GABA)ergic (Ohnuma et al., 1999; Blatt et al., 2001; Volk et al., 2002; Samaco et al., 2005; Guptill et al., 2007; Bullock et al., 2008; Fatemi et al., 2009c, 2009d, 2010a, 2011a, 2013a, 2013b; Beneyto et al., 2011; Glausier and Lewis, 2011), glutamatergic (Breese et al., 1995; Fatemi and Folsom, 2011; Fatemi et al., 2011b, 2013a), fragile X mental retardation (FMRP)–metabotropic glutamate receptor 5 (mGluR5) (Fatemi et al., 2010b, 2011b, 2013a, 2013c; Fatemi and Folsom, 2011; Kovács et al., 2013; Kelemen et al., 2013; Folsom et al., 2015), and Reelin (Impagnatiello et al., 1998; Guidotti et al., 2000; Keller et al., 2000; Fatemi et al., 2001; Lugli et al., 2003). These signaling systems are interconnected with each other, playing important roles during development including formation of correct lamination of the brain and neuronal migration (Reelin), proper excitatory/inhibitory signaling (glutamatergic/GABAergic), and regulation of protein translation (FMRP). Impairments in one system could impact other systems, ultimately resulting in deficits associated with major psychiatric disorders (Estes and McAllister, 2016).
Previous data from our laboratory demonstrated that Reelin immunoreactivity was reduced in brains of the offspring of exposed mice (Fatemi et al., 1999). Additionally, we demonstrated reduced Reelin expression in brains of subjects with autism and schizophrenia (Fatemi et al., 2000), two neurodevelopmental disorders that are successfully modeled by this mouse model of prenatal viral infection. Similar to Reelin, previous data from our laboratory demonstrated altered expression of GAD65/67 kDa and GABAA and GABAB receptor subunits in brains of subjects with autism and schizophrenia (Fatemi et al., 2002b, 2009c, 2009d, 2010a, 2013a), prompting us to determine whether these molecules also display an altered expression in the brains of the offspring of exposed mice. The GABAergic and FMRP‐mGluR5 signaling systems are also intertwined. FMRP downregulation in animal models of fragile X syndrome (FXS) has been accompanied by reduced expression of multiple GABAA receptor subunits (El Idrissi et al., 2005; D'Hulst et al., 2006; Gantois et al., 2006; Adusei et al., 2010; Hong et al., 2012), and FMRP has been shown to co‐localize with GABAA receptors (Frederikse et al., 2015).
An important but neglected site of synaptic and memory‐related tasks is the cerebellum.