Source: Okayama University (JAPAN), Public Relations Division
For immediate release: 27 October 2020
Okayama University research: Making memories—the workings of a neuron revealed
(Okayama, 27 October) In a study published in Scientific Reports
researchers at Okayama University use simulations to depict changes
that occur within neurons during the processes of learning and memory
formation.
Two antagonist phenomena in the brain are known to drive learning and
memory. Long-term potentiation (LTP) strengthens communication between
adjacent neurons to facilitate the integration of new memories.
Long-term depression (LTD) weakens such interactions to relieve the
brain of redundant information. However, the molecular changes driving
these processes are still unclear to neuroscientists. Now, in a
collaboration between Associate Professor SUMI Tomonari from Okayama
University and Assistant Professor HARADA Kouji from Toyohashi
University of Technology, a pair of scientists has revealed how the
competitive shuttling of one molecule between in and out of synapses
play an important role in this regard.
LTP and LTD are initiated by flux of calcium ions into neighbouring
(post-synaptic) neurons when those receive signals from the pre-synaptic
ones. The post-synaptic neurons then do so by presenting a signal
reader known as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor (AMPAR) on their surface during LTP, which fades away during
LTD. To understand the dynamics of AMPAR increase and decrease on
post-synaptic membranes better, the duo created a mathematical model of
post-synaptic neuron that closely mimicked physiological LTP and LTD.
Neurons of the hippocampus—the seat of learning and memory within the
brain—were used as a model system.
Influxes of calcium ions were applied as the input of the simulations,
and successfully trigger LTP and LTD. As expected, calcium-induced LTP
stimulus resulted in AMPAR being shuttled out of the post-synaptic
neurons, whereas LTD resulted in AMPAR being shunted back in. A deeper
dive revealed that two opposing calcium sensors, namely synaptotagmin
1/7 (Syt1/7) and protein interacting with C-kinase 1 (PICK1), were
driving these movements. Both sensors were active during LTP and LTD
albeit in varying amounts. The Syt1/7 activity overtook the PICK1 during
LTP resulting in a release of AMPAR from vesicles, whereas the former
was overtook by the latter during LTD resulting in a recapture of the
released AMPAR. A competition between Syt1/7 and PICK1 was thus behind
the increase and decrease of AMPAR on the post-synaptic membranes.
The research duo then closely examined the fate of AMPAR once it was
shunted back into post synaptic neurons. Instead of degrading, AMPAR
was stored in little vesicles near the neuron surface and kept ready for
the next LTP signal. This resulted in an almost instantaneous
incorporation of AMPAR into the postsynaptic membranes upon LTP
stimulus. Myosin Vb, a molecular motor protein, was responsible for this
dynamic recycling of AMPAR within the neuron.
This study showed two competing mechanisms underlying LTP and LTD
instead of two mutually exclusive processes. Additionally, the role of
key molecules driving this dynamic competition was revealed. Deciphering
the complexities of LTP and LTD is instrumental in understanding memory
related disorders such as Alzheimer’s disease and amnesia.
Background
LTP, LTD, and AMPAR: Long-term potentiation (LTP) is the strengthening,
and long-term depression (LTD) is the weakening of inter-neuron
connections in response to chemicals known as neurotransmitters. The
chemically induced inflow of calcium ions into adjacent (post-synaptic)
neurons warns to prepare for either LTP or LTD. Subsequently, the
initiating (pre-synaptic) neuron fires neurotransmitters such as
glutamate to communicate with the post-synaptic neurons.
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) is a
molecule that closely resembles glutamate. Thus, the post-synaptic
neuron presents the AMPA receptor (AMPAR) on its surface to read
glutamate signals. LTP leads to more AMPAR incorporation into
postsynaptic membranes and better glutamate binding, whereas LTD leads
to the opposite. The increase and decrease of AMPAR on post-synaptic
membranes is a key factor in facilitating neuronal connections.
Understanding the dynamics of AMPAR shuttling is vital for research on
the normal development of learning and memory and disorders that
implicate them.
Reference
Tomonari Sumi, Kouji Harada. Mechanism underlying hippocampal long-term
potentiation and depression based on competition between endocytosis and
exocytosis of AMPA receptors. Scientific Reports, volume.10, Article
number: 14711 (2020)
DOI : 10.1038/s41598-020-71528-3
https://www.nature.com/articles/s41598-020-71528-3#citeas
Correspondence to
Associate Professor SUMI Tomonari, Ph.D.
Research Institute for Interdisciplinary Science, Okayama University,
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
e-mail : sumi(a) cc.okayama-u.ac.jp
For inquiries, please contact us by replacing (a) with the @ mark.
http://www.cc.okayama-u.ac.jp/~sumi/index_e.html
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