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N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in synapses on hippocampal excitatory neurons are considered to be a molecular basis essential to form the neural circuits involved in learning and memory. In mammalians, it has been proved that the main factor of the induction of LTP and LTD results in an increase and decrease in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) at the postsynaptic membrane, depending on the calcium ion volume. However, the mechanism of the fluctuation of the AMPAR has not been elucidated. In addition, the true nature of the main pathway for AMPAR trafficking to the postsynaptic membrane remains up for debate as can be seen in the following studies.

Penn, et al. showed that the long-range lateral diffusion of AMPAR directed from areas other than the postsynaptic membrane (e.g. dendrite shaft) to the postsynaptic membrane is the main pathway for AMPAR trafficking for the LTP [1], and the long-range lateral diffusion pathway has been considered to be the most likely candidate as the main pathway. On the other hand, Wang et al. demonstrated the importance of the active transport of recycling endosomes containing AMPAR by molecular motor myosin V_b [2], and Wu et al. observed the exocytosis of the recycling endosomes containing AMPAR during the induction of LTP [3]. These studies embodied the elemental processes of AMPAR trafficking via the recycling endosome pathway. Currently, it is still unknown which pathway for AMPAR trafficking is the main one, but since all of these studies basically focus on the induction of LTP, there remains a need for an explanation of the pathway including the induction of LTD without inconsistency.

Assistant Professor Harada and Associated Professor Sumi modeled the following 4 processes of “active” transport of recycling endosomes containing AMPAR by molecular motor myosin V_b as a pathway for AMPAR trafficking to the postsynaptic membrane in order to comprehensively explain the LTP/LTD (Fig.1).

• AKAP150 signaling complex controlling the phosphorylation/dephosphorylation of subunits, GluA1 and GluA2, that constitute AMPAR (Upper left of Fig.1)
• Endocytosis of AMPAR to the cytoplasm by a calcium-binding protein, PICK1 (Upper right of Fig.1)
• Stationary active transport of recycling endosomes containing AMPAR toward postsynaptic membranes by myosin V_b (Lower right of Fig.1)
• AMPAR uptake at around postsynaptic membranes by Syt1/7-dependent exocytosis (Lower left of Fig.1)

A simulation using a postsynaptic model based on these processes successfully reproduced the time course of the number of AMPAR corresponding to the induction of LTD and LTD observed in the experiment (Lower right of Fig. 2). In addition, the qualitative reproducibility of certain results demonstrated the validity of the model. These results include impaired LTP induction due to interference of Myosin V_b transport, impaired LTD induction due to decreased rate of reaction of PP2B-dependent dephosphorylation of AMPAR, impaired LTP and LTD inductions due to PICK1 expression level, and impaired LTP induction in Syt1 calcium-binding domain mutant.

The conclusions drawn from this simulation are as follows.

1. The LTP (or LTD) expression is caused by a phenomenon whereby the exocytosis triggered by the activation of Syt1/7 becomes more predominant (or inferior) than the endocytosis triggered by PICK1 activation, resulting in an increase (or decrease) in the number of AMPAR at the postsynaptic membrane.
2. The difference in calcium-dependent activation between the calcium sensors, PICK1 and Syt1, results in a difference in these calcium-binding constants.
3. Myosin V_b carries the recycling endosomes containing AMPAR toward around the postsynaptic membrane by stationary ATP driven transport not dependent on calcium concentration.
4. As a result, the recycling endosomes are waiting on cell membranes so that they can immediately address the next Syt1-dependent exocytosis, enabling the rapid LTP induction.
5. AMPARs taken up to around the postsynaptic membrane due to exocytosis are immediately reallocated to the synapse membrane by the lateral diffusion.

The neural network model mimicking the higher brain function can learn changes of synapse coupling coefficient, and Hebbian rule is known as a most basic learning rule. The Hebbian rule and its extended/modified versions are currently used as learning rules, which are known to be closely related to NMDAR-dependent LTP. The achievement of this study provides a molecular basis for the Hebbian rule or changes of synapse binding, which is expected to be a hint to understand the high brain function from the molecular level.

This study was supported by the Grants-in-Aid for Scientific Research of Japan Society for the Promotion of Science (JSPS) (JP16K05657, JP18KK0151, JP16K00389).