Neurogenetic mechanisms of seizure and adaptive social behavior in Drosophila melanogaster

Abstract

Drosophila melanogaster is a powerful model for neurogenetic research due to its well-defined genetics and the availability of sophisticated gene manipulation tools. Importantly, Drosophila shares significant genetic similarities with humans, making it an excellent model for studying conserved neural mechanisms relevant to physiology. Its relatively simple neural circuits and advanced genetic techniques allow precise mapping of neurons involved in distinct Drosophila behaviors. The neurogenetic manipulations enable me to dissect how genetic and environmental factors influence complex behaviors, providing insights into the neural regulation of behavior and the genetic basis of neurological disorders. However, despite its strengths, previous research has often been limited by the lack of a clear mechanistic understanding of how specific genetic pathways impact neurological conditions such as seizure and adaptive social behavior, necessitating further investigation into these areas. Kohlschütter-Tönz syndrome (KTS) is a neurodevelopmental disorder characterized by early-onset seizures and neurological dysfunction. KTS has been shown to be associated with mutations in the citrate transporter gene SLC13A5, but the exact mechanisms linking these mutations to seizure susceptibility remain unclear. I demonstrate that a Drosophila homolog of SLC13A5, known as I’m not dead yet (Indy), plays a crucial role in a neurometabolic pathway for seizure suppression. The Indy gene encodes a citrate-Na⁺ transporter that regulates tricarboxylate intermediates essential for maintaining metabolic balance in neurons. Loss of Indy function in glutamatergic neurons resulted in bang-induced seizure-like behaviors due to reduced glutamate biosynthesis from the citric acid cycle. Interestingly, supplementing these flies with α-ketoglutarate, a critical metabolic intermediate, restored glutamate levels and mitigated seizure-like behaviors. The Indy-dependent seizure control was mapped to specific glutamatergic neurons expressing the neuropeptide leucokinin (LK). In fact, LK has been implicated in modulating neuronal activity and influencing diverse physiological processes such as regulating satiety. LK neurons regulated seizure dynamics by relaying their glutamatergic transmission to the downstream brain locus designated as the dorsal fan-shaped body via the ionotropic glutamate receptor, revealing a metabolic-neural circuit that regulates seizure susceptibility. In addition to seizure studies, Drosophila has been instrumental in understanding social behavior. Although Drosophila forms social clusters, the genetic and neural mechanisms governing these social interactions have been poorly understood. To address this, I performed a systematic analysis of social network behavior (SNB) by examining social distance (SD) in 175 inbred strains from the Drosophila Genetics Reference Panel (DGRP). I found that flies with shorter SDs displayed longer developmental periods, lower food intake, and reduced activity. Living in groups alleviated these developmental challenges, whereas isolation during development abolished the benefits of social interactions and reduced SNB plasticity under physiological stress. Transcriptomic analysis revealed genetic diversity underlying SD traits, with social isolation reprogramming specific genetic pathways, including the downregulation of Drosulfakinin (Dsk). The neuropeptide DSK is a Drosophila homolog of mammalian cholecystokinin that modulates distinct animal behaviors through its signaling via the DSK receptor Cholecystokinin-like-receptor 17D1 (CCKLR-17D1). My data demonstrate that male-specific DSK signaling modulates SNB plasticity, and manipulating DSK neuron activity was sufficient to replicate the effects of social experience. These findings highlight an evolutionarily conserved mechanism that encodes early-life experiences and shapes adaptive social behavior. In summary, my research uncovers key neurometabolic and neurogenetic mechanisms that influence seizure susceptibility and social behavior in Drosophila melanogaster. I found that the Indy plays a critical role in seizure suppression by regulating glutamate biosynthesis, with α-ketoglutarate supplementation mitigating seizure-like behaviors. Additionally, shorter SDs were linked to developmental delays, reduced activity, and altered expression of the neuropeptide DSK. Social isolation reprogrammed key genetic pathways, disrupting social behavior plasticity. These findings provide insights into conserved genetic mechanisms governing neural function and behavior, with implications for human neurological disorders.