Abstract
Dlx5 and Dlx6 encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During development, Dlx5/6 play a role in the differentiation of certain GABAergic subclasses. Here we address the question of the functional role of Dlx5/6 in the mature central nervous system. First, we demonstrate that Dlx5 and Dlx6 are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyze VgatΔDlx5-6 mice in which Dlx5 and Dlx6 are simultaneously inactivated in all GABAergic interneurons. VgatΔDlx5-6mice present a behavioral pattern suggesting reduction of anxiety-like behavior and obsessive-compulsive activities, and a lower interest in nest building. Twenty-month-old VgatΔDlx5-6 animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, both VgatΔDlx5-6/+ and VgatΔDlx5-6 mice present a 33% longer median survival. Hallmarks of biological aging such as motility, adiposity and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate healthspan and lifespan through Dlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.
Highlights
Brain activity depends on GABAergic inhibitory interneurons, a heterogeneous class of neurons distinguished by diverse anatomical, biochemical and physiological characteristics [1]
The main finding of this study is that transcriptional modifications limited to GABAergic neurons are sufficient to prolong healthspan and lifespan
We have shown that inactivation of the two transcription factors Dlx5 and Dlx6 in mouse GABAergic interneurons produces behavioral and metabolic changes accompanied by a prolonged median survival in good health
Summary
Brain activity depends on GABAergic inhibitory interneurons, a heterogeneous class of neurons distinguished by diverse anatomical, biochemical and physiological characteristics [1]. Three major classes of GABAergic neurons expressing Parvalbumin (Pvalb), Somatostatin (Sst) and 5HTr3A respectively have been described, the extent of GABAergic cellular diversity begins only recently to be appreciated thanks to single cell transcriptomic analysis [6, 7]. To generate these diverse morphotypes, neuronal progenitors engage in stereotyped transcriptional trajectories in which combinatorial sequences of transcription factors (TFs) progressively unfold specific differentiation programs [8]. We conclude that Dlx5/6-dependent regulations in GABAergic interneurons affect behavior as well as metabolism, and contribute to determine healthspan and lifespan
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