Study connects neural gene expression differences to functional distinctions

Figuring out how hundreds of different kinds of brain cells develop from their unique expression of thousands of genes promises to not only advance understanding of how the brain works in health, but also what goes wrong in disease. A new MIT study that precisely probes this “molecular logic” in two neuron types of the Drosophila fruit fly shows that even similar cells push and pull many levers to develop distinct functions.

In the study in Neuron, a team of neurobiologists at The Picower Institute for Learning and Memory found that the two closely related neuronal subtypes differed from each other in how they expressed more than 800 genes, or about 5 percent of the total genes encoded in the fly genome. By manipulating genes whose expression differed most prominently, the scientists were then able to show how they produced several of the observable differences between the cells.

The two neuron types compared in the study both emerge from the fly’s analog of a spinal cord to control muscles by releasing the neurotransmitter glutamate at connections called synapses. The neurons’ main functional differences are that “phasic” neurons connect to many muscles and emit big, occasional bursts of glutamate, while “tonic” neurons each connect to only one muscle and provide more of a constant drip of the chemical. This duality, which is also found in neurons of the human brain, provides a flexible range of control.

Picower Institute postdoc Suresh Jetti led the effort in Littleton’s lab to determine how these two neurons develop their differences. The team began with an unusually deep characterization of how the two cell types differ in form and function and then took a highly precise look at the gene expression profiles, or transcriptomes.

A particularly new and intriguing finding was that the AZs in tonic and phasic neurons took on different shapes. Tonic AZs were round, like donuts, while phasic ones were more triangular or star-shaped. Littleton hypothesizes that this difference could allow for more calcium ions to crowd into the phasic active zones, perhaps explaining their greater bursts of glutamate release compared to tonic neurons.

To assess gene expression, Jetti employed a technique called “isoform patchseq,” in which he identified the exact same tonic and phasic neurons in hundreds of flies and extracted RNA from their individual nuclei and cell bodies. The technique, while very hard work, provided the team with an unusually rich vein of transcriptomic information from precisely the cells of interest, Littleton says, including not only how gene expression differed between the two cell types, but also how gene splicing and RNA editing were different.

In all, the expression of 822 genes was significantly different between the two neuron types. About 35 of the genes were known to help guide the growth of the axon branches that neurons extend to forge their connections with muscle — a set of differences pertinent to why tonic neurons innervate only one muscle while phasic ones innervate many. Other differentially expressed genes related to the structure and function of synapses, while more than 20 others suggested differences in the neuromodulatory chemicals each neuron was sensitive to as inputs.

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