Summary: New research reveals unexpected molecular steps that enable memories to form at the level of single synapses.
Source: Duke
Mouse study uncovers surprising molecular choreography behind memory formation
We remember spectacular moments, like Simone Biles’s celebrated gymnastics routine, because our brains physically strengthen specific synapses — the tiny contact points between neurons. A joint study from Duke University and the Max Planck Florida Institute for Neuroscience reveals surprising molecular processes that drive those changes. Published online September 28 in Nature, the findings also have implications for understanding how certain diseases, including forms of epilepsy, develop.
“These results help us begin to unravel how a normal brain encodes memory and how those same mechanisms may be hijacked in epilepsy,” said co-senior author James McNamara, M.D., professor of neurobiology and neurology at Duke.
When we form a memory, particular synapses strengthen and the postsynaptic structure — a small protrusion called a dendritic spine — enlarges. Previous work suggested the receptor TrkB plays a role in spine growth, and this new study confirms TrkB’s essential involvement while detailing how it is activated during learning-like events.
Key to the discovery were a set of advanced tools: a fluorescence sensor engineered to detect TrkB activity, two-photon microscopy capable of imaging single spines in living mouse hippocampal tissue, and a technique to deliver tiny, controlled amounts of glutamate directly to one spine to mimic synaptic activation. When researchers uncaged glutamate at a single spine, that spine enlarged — a hallmark of synaptic strengthening.
Crucially, when TrkB was absent or blocked, the spine did not grow in response to the glutamate stimulus, demonstrating that TrkB activation at the postsynaptic site is required for spine enlargement.
The investigators also explored the role of brain-derived neurotrophic factor (BDNF), the ligand that activates TrkB. By building a molecular sensor for BDNF, they found that a learning-like stimulus triggers release of BDNF from the postsynaptic dendritic spine itself. This finding was unexpected because the prevailing view held that BDNF is released only from the presynaptic (sending) neuron.
“The fact that the receiving neuron both releases BDNF into the synaptic cleft and responds to it locally is highly unusual in biological terms,” said co-senior author Ryohei Yasuda, scientific director at the Max Planck Florida Institute for Neuroscience. He noted that postsynaptic BDNF release might influence several nearby cells and that the team will continue to probe how that broader signaling is organized.
Although these experiments were performed in mice, the BDNF–TrkB interaction is likely conserved in humans and therefore fundamental to learning and memory. The same molecular pathway may also contribute to temporal lobe epilepsy (TLE), a common epilepsy that affects brain regions involved in memory.
Some instances of TLE begin after a single, prolonged seizure early in life. During such episodes, glutamate — the same neurotransmitter used in normal synaptic plasticity — is released at much higher levels and for longer durations. Prior work from McNamara’s lab indicates that TrkB is essential for the development of TLE, and that transient inhibition of TrkB signaling following the initial seizure can prevent TLE in mice.
The team is now investigating the downstream events triggered by TrkB activation that lead individual spines to grow, and they are searching for additional mechanisms that might contribute to TrkB activation in both learning and pathological conditions.
Funding: Supported by the National Institutes of Health (F31NS078847, R01NS068410, DP1NS096787, R01NS05621, R01MH080047, R01DA08259, R01HL098351, P01HL096571, and RO1NS030687), the Wakeman Fellowship, and the Human Frontier Science Program.
Source: Kelly Rae Chi – Duke
Image source: This NeuroscienceNews.com image is in the public domain.
Original research: “Autocrine BDNF–TrkB signalling within a single dendritic spine” by Stephen C. Harward, Nathan G. Hedrick, Charles E. Hall, Paula Parra-Bueno, Teresa A. Milner, Enhui Pan, Tal Laviv, Barbara L. Hempstead, Ryohei Yasuda & James O. McNamara. Nature. Published online September 28, 2016. DOI: 10.1038/nature19766
Autocrine BDNF–TrkB signalling within a single dendritic spine
BDNF and its receptor TrkB are essential for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), a cellular correlate of learning. Until now it was unclear whether BDNF is released and whether TrkB is activated locally during sLTP. Using a TrkB fluorescence resonance energy transfer sensor together with two-photon fluorescence lifetime imaging, the authors monitored TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured mouse hippocampal slices. Following sLTP induction, TrkB showed rapid (onset under one minute) and sustained (greater than 20 minutes) activation in the stimulated spine. This activation depended on N-methyl-D-aspartate receptor (NMDAR) and CaMKII signaling and required postsynaptically synthesized BDNF. Electron microscopy confirmed endogenous BDNF in dendrites and spines of CA1 neurons, and imaging of BDNF fused to a pH-sensitive reporter demonstrated rapid, time-locked BDNF release from single spines in response to glutamate uncaging. The study shows that this postsynaptic, autocrine BDNF–TrkB signaling pathway is necessary for both structural and functional LTP, revealing a spine-autonomous mechanism in which NMDAR–CaMKII-dependent BDNF release and subsequent TrkB activation drive synaptic plasticity.