GABAergic neurons regulate lateral ventricular development via transcription factor Pax5

Abstract

Postmortem studies have revealed a downregulation of the transcription factor Pax5 in GABAergic neurons in bipolar disorder, a neurodevelopmental disorder, raising the question whether Pax5 in GABAergic neurons has a role in normal brain development. In a genetic approach to study functions of Pax5 in GABAergic neurons, Pax5 was specifically deleted in GABAergic neurons from Pax5 floxed mice using a novel Gad1-Cre transgenic mouse line expressing Cre recombinase in Gad1-positive, i.e. GABAergic neurons. Surprisingly, these mice developed a marked enlargement of the lateral ventricles at approximately seven weeks of age, which was lethal within 1-2 weeks of its appearance. This hydrocephalus phenotype was observed in mice homozygous or heterozygous for the Pax5 conditional knockout, with a gene dosagedependent penetrance. By QTL (quantitative trait loci) mapping, a 3.5 Mb segment on mouse chromosome 4 flanked by markers D4Mit237 and D4Mit214 containing approximately 92 genes including Pax5 has previously been linked to differences in lateral ventricular size. Our findings are consistent with Pax5 being a relevant gene underlying this QTL phenotype and demonstrate that Pax5 in GABAergic neurons is essential for normal ventricular development.

Gestational diabetes exacerbates maternal immune activation effects in the developing brain

“…Three hours following injection, poly(I:C) treatment in the context of GDM produced marked induction of many inflammation and neurodevelopment genes (Figure 3C). GDM+MIA both induced ( Foxg1, Gad1, Vamp1 ) and repressed ( En1, En2, Fgf8, Pax5 ) subsets of neurodevelopment genes involved in patterning and migration 50, 52–54 . Moreover, both the constitutively expressed GLUT1 and high affinity neuronal specific GLUT3 genes ( Slc2a1, Slc2a3 ) and hypoxia-associated Vegfa were induced in GDM+MIA.…”

Recurrent de novo mutations implicate novel genes underlying simplex autism risk

“…PAX5 , paired box protein 5, is a transcription factor and has been shown as significantly downregulated in bipolar disorder postmortem hippocampal extracts 32 . Conditional knockout of Pax5 in GABAergic neurons in mice highlight the necessity for this gene in normal ventricular development 33 further promoting a specific role for Pax5 in the etiology of ASD. Preliminary analysis based on existing data shows TRIP12 mutation carriers all have ASD and ID ranging from mild to moderate severity while the individuals with PAX5 demonstrate a higher range of cognitive ability from borderline to average intelligence concomitant with ASD.…”

Mice Deficient in Transmembrane Prostatic Acid Phosphatase Display Increased GABAergic Transmission and Neurological Alterations

“…However, enlarged ventricles were only observed in PAP −/− mice compared to WT mice. Additionally, it has been shown that GABAergic neurons regulate lateral ventricular development [32] .…”