Graphic by Rafeeque Mavoor

On any given day you get to work, park your vehicle, meet a colleague, surprise an old friend or taste vada pav for the first time. Only some of these experiences will become memories that will last a lifetime. This information is stored as changes in a part of the brain called the hippocampus. Specifically, connections or synapses between neurons that get activated become stronger or weaker during an ongoing experience. These changes in synaptic strength known as Long Term Plasticity (LTP) are triggered by calcium ions and carried out by several chemical signals.

Synaptic strengthening leads to memory storage

A crucial requirement for LTP is to be stable and last long after the chemical signals that caused it have subsided. This is the initial and necessary imprint in the hippocampus of an experience right before it gets transferred to other brain areas for long-term storage. Synaptic strengthening happens in the form of increases in size and greater responsiveness to ongoing activity in synapses that were active during the experience (corresponding decrease in size and responsiveness for weakening).

However this form of synaptic strengthening is inherently unstable. More responsive synapses are likely to be more active leading to further strengthening. This positive feedback loop can drive synaptic strengths to saturate, making them useless for future use in initiating new memories. Given the rich diversity of our experiences, a 100 billion neurons with 10,000 synapse that each can make, can still limit our ability to remember.

What happens when synaptic strengths saturate

Dr Suhita Nadkarni’s group constructed a physiologically realistic computational model of the synapses in the hippocampus to address an important question in the field of synaptic plasticity: How do synapses in the hippocampus counter this storage limitation, to ensure that plasticity occurs in a constrained manner so as to curb runaway strengthening? In other words, how does the brain make sure that it does not run out of storage space and continues to make long lasting memories?

“Although there is a clear functional need to rein in synaptic plasticity, there is limited understanding of the underlying molecular components that can coordinate it”, says postdoctoral researcher Gaurang Mahajan and author on this recently published paper. Here, Mahajan and Nadkarni propose a novel form of metaplasticity linked to the release of calcium from the endoplasmic reticulum (ER) in these synapses. The ER is a system of continuous membranes within the cell; the ER serves as an intracellular store of calcium and also coordinates multiple other functions.

The role of endoplasmic reticulum (ER) of the cell in plasticity

Through extensive numerical simulations of different plasticity protocols, the team has characterized how changes in local calcium release, due to the presence of the ER in the synapse, alter plasticity induction.

A key finding of their analysis is that the ER modulates plasticity in a manner that selectively promotes weakening of synapses. The team proposes that the presence of the ER promotes re-use of hippocampal synapses with saturated strengths. Curiously, the ER is rarely observed in small weak synapses, but is present in majority of large strong synapses implying their readiness for reuse.

“Given that ER-containing spines tend to be sites of stronger synaptic contacts, our results suggest that targeting of the ER to strengthened synapses may act as a “metaplastic switch”. This could be regulating the threshold for subsequent plasticity and mitigating the propensity for further strengthening of the synapse”, says Dr Nadkarni on the implications of their results in our understanding of synapse strength and memory storage.

Small sizes of the synaptic compartments make it difficult to make measurements at a single synapse and most experimental investigations are carried out with combined electrical activity of several hundred synapses. Since occurrence of the ER is limited only to large synapses, this makes it difficult to assess its precise contribution to synaptic signaling and function from population level studies of synapses. This underscores the value of a computational modeling approach that the current study has implemented for elucidating the role of the ER in microdomain signaling at the level of individual synapses.

“This study takes the concept of plasticity-stability balance at synapses beyond the existing theoretical frameworks for plasticity and demonstrates a physiologically plausible way for individual synapses of the hippocampus to achieve the balance”, adds Dr Nadkarni.

This work has been published in the Journal of Physiology and is authored by Gaurang Mahajan and Suhita Nadkarni. This research received funding from Wellcome Trust/DBT India Alliance and DST’s Science & Engineering Research Board.

- With inputs from Dr. Suhita Nadkarni