Mechanism Underlying Hippocampal Post-Tetanic Potentiation

Post by Shireen Parimoo 

What's the science?

Short-term memories are memories that can persist for several minutes and are formed in the hippocampus. Post-tetanic potentiation (PTP) at hippocampal mossy fiber synapses between granule cells and CA3 neurons is a potential candidate to support the formation of short-term memories. PTP is a type of synaptic plasticity that occurs in response to high-frequency stimulation (HFS). In a synapse in the auditory system, for example, HFS results in PTP by increasing the probability of vesicle release from the pre-synaptic neuron. However, it is not known how PTP occurs at hippocampal mossy fiber synapses. This month in Neuron, Vandael and colleagues used electrophysiological recordings and functional electron microscopy to examine the structural and functional mechanisms underlying PTP generation in the rodent hippocampus.

How did they do it?

First, the authors characterized spiking activity in the hippocampal granule cells of head-fixed mice using in vivo electrophysiological recordings. They stimulated single mossy fiber boutons and recorded excitatory post-synaptic currents at the level of CA3 neurons to determine if PTP occurs at the unitary level. They then compared the magnitude of PTP resulting from naturally occurring activity using standard HFS protocols. They identified the threshold for PTP induction in vitro and tested if granule cell superburst activity would suffice to induce PTP.

Next, the authors investigated two possible mechanisms underlying PTP: (i) an increase in the probability of vesicle release from the pre-synaptic terminal, and/or (ii) an increase in the size of the pool of pre-synaptic vesicles available for release, or the ‘readily-releasable pool’. They applied HFS stimulation at the level of single mossy fiber terminals and measured changes in excitatory post-synaptic currents to quantify the size of the vesicle pool and the probability of vesicle release. A structural correlate of the readily-releasable pool is the pool of vesicles docked at the active zone in the presynaptic terminal. Thus, they used flash and freeze electron microscopy to explore whether more docked vesicles would be available for release after PTP induction. Specifically, they optogenetically stimulated mossy fiber terminals, froze them immediately or after a 20-second delay, and recorded the number of docked vesicles using electron microscopy. Lastly, to explore the physiological relevance of PTP, they applied HFS to induce PTP and then measured if the potentiation could still be observed after delays of up to 5 minutes.

What did they find?

In active hippocampal granule cells, natural activity is composed of single action potentials, bursts, and/or “superbursts” (i.e. bursts of bursting activity). Superburst patterns in vivo were strong enough to induce PTP at mossy fiber boutons in vitro. Moreover, PTP was accompanied by a large increase in the size of the readily-releasable pool, whereas the probability of vesicle release did not change significantly. There was also a reduction in the number of docked vesicles immediately after HFS, but at a 20 second delay after PTP induction, both the number and size of the docked vesicles increased. Thus, HFS induces PTP by altering the number of vesicles available for release at the pre-synaptic terminal, which effectively forms an engram (i.e. a memory trace). The effects of PTP on neural activity and the size of the vesicle pool decayed over time in response to additional stimulation. Interestingly, however, the absence of pre-synaptic activity following PTP induction did not abolish PTP, suggesting PTP is preserved by saving the extra vesicles for release for an extended period of time.

What's the impact?

This study is the first to identify the mechanism underlying post-tetanic potentiation in the mossy fiber pathway of the rodent hippocampus. These findings provide a deeper insight into our understanding of how hippocampal PTP might potentially enable the formation of short-term memories.

Vandael et al. Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation. Neuron (2020). Access the original scientific publication here.