Dlx5/6 Expression Levels in Mouse GABAergic Neurons Regulate Adult Parvalbumin Neuronal Density and Anxiety/Compulsive Behaviours.

Neuronal circuits integrating Parvalbumin-positive GABAergic inhibitory interneurons (PV) are essential for normal brain function and are often altered in psychiatric conditions. During development, Dlx5 and Dlx6 (Dlx5/6) genes are involved in the differentiation of PV-interneurons. In the adult, Dlx5/6 continue to be expressed at low levels in most telencephalic GABAergic neurons, but their importance in determining the number and distribution of adult PV-interneurons is unknown. Previously, we have shown that targeted deletion of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in altered behavioural and metabolic profiles. Here we evaluate the consequences of targeted Dlx5/6 gene dosage alterations in adult GABAergic neurons. We compare the effects on normal brain of homozygous and heterozygous (Dlx5/6VgatCre and Dlx5/6VgatCre/+ mice) Dlx5/6 deletions to those of Dlx5 targeted overexpression (GABAergicDlx5/+ mice). We find a linear correlation between Dlx5/6 allelic dosage and the density of PV-positive neurons in the adult prelimbic cortex and in the hippocampus. In parallel, we observe that Dlx5/6 expression levels in GABAergic neurons are also linearly associated with the intensity of anxiety and compulsivity-like behaviours. Our findings reinforce the notion that regulation of Dlx5/6 expression is involved in individual cognitive variability and, possibly, in the genesis of certain neuropsychiatric conditions.

DLX5/6 GABAergic Expression Affects Social Vocalization: Implications for Human Evolution.

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated with neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioral and metabolic phenotypes notably increasing lifespan by 33%. Here, we show that Dlx5/6VgatCre mice present a hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10 min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1,400 calls/10 min with a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals. The characters affected by Dlx5/6 in the mouse (sociability, vocalization, skull, and brain shape…) overlap those affected in the "domestication syndrome". We therefore explored the possibility that DLX5/6 played a role in human evolution and "self-domestication" comparing DLX5/6 genomic regions from Neanderthal and modern humans. We identified an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype includes the binding site for GTF2I, a gene associated with Williams-Beuren syndrome, a hyper-sociability and hyper-vocalization neurodevelopmental disorder. The DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105 years of age), a well-established human model of healthy aging and longevity, suggesting their involvement in the coevolution of longevity, sociability, and speech.