New Role for Leptin: Promoting Synapse Formation in Rat Neurons

ABOVE: Rat hippocampal neurons labeled purple with likely GABAergic synapses labeled blue
G.S. SAHIN ET AL. SCI SIGNAL, DOI:10.1126/scisignal.abe4111, 2021.

Leptin is a hormone released by fat cells in adult organisms, and researchers have largely focused on how it controls appetite. In a study published May 18 in Science Signaling, the authors show that leptin promotes synapse formation, or synaptogenesis, in developing rodent neurons in culture.

“This paper does a really wonderful job [breaking] down the mechanisms” of leptin signaling, and the authors look at changes in synaptic function, not just at the protein level, but also on a physiological level, says Laura Cocas, a neuroscientist at Santa Clara University who was not involved in the study. “Because all of the work on the paper is done in vitro, they can do very careful analysis . . . to break down each step in the signaling pathway.”

When Washington State University neuroscientist Gary Wayman and his group started working on leptin about 10 years ago, most of the research had examined the hormone’s function in regulating satiety. But “we and others knew that leptin surged during a critical period of neuronal—and in particular synaptic—development in the brain,” he says. In people, this surge happens during the third trimester of fetal development and, in rodents, over the first few weeks of life. “This surge in leptin is independent of the amount of adipose tissue that’s present. And it does not control feeding during this period because feeding circuits have not developed, so we really wanted to understand what the developmental role was.”

Everybody has been talking about [leptin] really as largely a factor that regulates feeding, so it is very surprising that we now know that it has a very important role in regulating the patterning and development of the brain.

—Gary Wayman, Washington State University

Wayman and colleagues focused on the hippocampus because, despite being one of the best-characterized regions in the brain, there wasn’t a lot of information out there about what the leptin receptors present were doing—particularly during development. Multiple groups had also shown that leptin injected in this brain region can improve cognition and act as an antidepressant.

The team treated cultured hippocampal neurons from one-day-old rat pups with leptin and found that it increased the presence of synapses that signal with the neurotransmitter gamma aminobutyric acid (GABA). To investigate the function of these so-called GABAergic synapses, the researchers treated rat and mouse pup brain slices with leptin and then made electrophysiological recordings of hippocampal neurons. They saw an increase in frequency and amplitude of GABAergic currents following treatment—an effect that the researchers blocked by knocking down the leptin receptor—indicating that leptin expands the number of GABA synapses and makes them more efficient.

Then the researchers looked into how leptin exerts these effects and determined that it increases interactions between the main GABA receptor on the postsynaptic neuron and another protein called β-PIX, which is known to regulate the actin cytoskeleton. They also showed that β-PIX forms a complex with the leptin receptor and that all these hook-ups facilitate the increase in GABAergic synapse formation seen during rodent neuron development in culture.

While it’s been suggested before that leptin supports the growth and survival of neurons, says Wayman, “everybody has been talking about it really as largely a factor that regulates feeding, so it is very surprising that we now know that it has a very important role in regulating the patterning and development of the brain.”

One outstanding question, according to Claire Cheetham, a neuroscientist at the University of Pittsburgh who was not involved in the study, is whether leptin plays a similar role in the adult brain—particularly in synaptogenesis in adult-born neurons, which generally happens in the hippocampus—and if so, whether the leptin-interacting molecules identified here also participate.

“During this period, the GABAergic synapse and activation of GABA receptor regulates other developmental events in the neuron—in particular, excitatory synapse development,” Wayman tells The Scientist. In the adult brain, GABA is the main inhibitory neurotransmitter, causing postsynaptic neurons to go quiet, but it excites immature neurons. Because leptin plays a role in GABAergic synaptogenesis, levels of the hormone during development could influence the formation of both inhibitory and excitatory synapses, as well as downstream cognition and emotional development. “There’s some intricate crosstalk between different synaptic elements,” Wayman notes. “And without this excitatory action of GABA, other important neuronal developmental steps do not occur.”

In the future, Wayman and colleagues will investigate whether these mechanisms influence autism, Fragile X syndrome, and Rett syndrome. “One of the main associated causes for most neurological disorders is defective synaptic development or synaptic connections,” he explains. “You need both the correct number of excitatory and inhibitory synapses, and you need those synapses to occur on the right target neurons.”