One of the hallmarks of Alzheimer’s disease is memory loss. Now, a new study by UCLA researchers has found that lost memories can be restored. The findings offer hope for individuals who suffer from the disease. The findings were published recently in the journal eLife.
The study authors note that for decades, it was believed that memories are stored at the synapses, which are the connections between brain cells, or neurons, and that these connections are destroyed by Alzheimer’s disease. Their new study offers evidence contradicting this concept that long-term memory is stored at synapses. “Long-term memory is not stored at the synapse,” noted senior author David Glanzman, PhD, a UCLA professor of integrative biology and physiology and of neurobiology, as well as a member of UCLA’s Brain Research Institute. He added, “That’s a radical idea, but that’s where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won’t be easy, but I believe it’s possible.”
The investigators are involved in studying a type of marine snail called Aplysia with the goal of understanding the animal’s learning and memory. The Aplysia exhibits a defensive response to protect its gill from potential harm; Dr. Glanzman and his team are particularly interested in its withdrawal reflex and the sensory and motor neurons that produce it. For the study, they subjected the snail’s tail to several mild electric shocks, which enhanced its withdrawal reflex. The enhancement lasts for days after a series of electrical shocks, which indicates that it is present in the snail’s long-term memory. Dr. Glanzman explained that the shock causes the hormone serotonin to be released in the snail’s central nervous system.
Dr. Glanzman noted that long-term memory is a function of the growth of new synaptic connections due to serotonin. When long-term memories are formed, the brain produces new proteins that are involved in making new synapses. If that process is disrupted as a result to a concussion or other injury, the proteins may not be produced and long-term memories cannot form. This explains why individuals cannot remember what happened moments before a concussion.
Dr. Glanzman noted, “If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn’t remember the training. However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later. In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn’t affect long-term memory. That’s true in the Aplysia and in human’s brains.” This explains why individual’s older memories typically survive following a concussion.
The researchers found the same mechanism also occurred when studying the snail’s neurons in a Petri dish. They placed the sensory and motor neurons that stimulate the snail’s withdrawal reflex in a Petri dish, where the neurons re-formed the synaptic connections that existed when the neurons were inside the snail’s body. When serotonin was added to the dish, new synapses formed between the sensory and motor neurons. However, if the addition of serotonin was immediately followed by the addition of a substance that inhibits protein synthesis, the new synaptic growth was blocked. As a result, long-term memory could not be formed.
The investigators also wanted to determine whether synapses disappeared when memories did. Thus, they counted the number of synapses in the dish and then, 24 hours later, added a protein synthesis inhibitor. One day later, they re-counted the synapses. They discovered that new synapses had grown and the synaptic connections between the neurons had been fortified. Thus, late treatment with the protein synthesis inhibitor did not disrupt the long-term memory. Dr. Glanzman noted that the process is quite similar to what happens in the snail’s nervous system during this type of simple learning.
The next phase of the study involved adding serotonin to a Petri dish containing a sensory neuron and motor neuron. One day later, the researchers added another brief pulse of serotonin, which reminded the neurons of the original training, and immediately afterward add the protein synthesis inhibitor. This time, they found that both synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training. This suggests that the “reminder” pulse of serotonin triggered a new round of memory formation, and that inhibiting protein synthesis during this “reconsolidation” erased the memory in the neurons.
The authors note that if the prevailing theory was true, that memories are stored in the synapses, they should have found that the lost synapses were the same ones that had formed in response to the serotonin. However, that is not what happened––they found that some of the new synapses were still present and some had vanished, and that some of the original ones had vanished, also.
Dr. Glanzman noted that there was no obvious pattern to which synapses stayed and which disappeared, which implied that memory is not stored in synapses. When the experiment was repeated in the snail, and the animal received a modest number of tail shocks, which do not produce long-term memory in a naive snail, the memory they thought had been completely destroyed returned. This finding implies that synaptic connections that were lost were apparently restored. Dr. Glanzman explained, “That suggests that the memory is not in the synapses but somewhere else. We think it’s in the nucleus of the neurons. We haven’t proved that, though.”
Dr. Glanzman noted that the research could have substantial implications for individuals stricken with Alzheimer’s disease. Specifically, just because the disease is known to destroy synapses in the brain does not mean that memories are destroyed. He said, “As long as the neurons are still alive, the memory will still be there, which means you may be able to recover some of the lost memories in the early stages of Alzheimer’s.” He also explained that in the later stages of the disease, neurons die, which probably means that the memories cannot be recovered.
The authors note that the cellular and molecular processes appear to be very similar between the marine snail and humans, even though the snail has approximately 20,000 neurons and humans have about 1 trillion. Neurons each have several thousand synapses. Dr. Glanzman formerly believed that traumatic memories could be erased but he has changed his mind. He now believes that, because memories are stored in the nucleus, it may be much more difficult to modify them. He plans to continue studying how the marine snail’s memories are restored and how synapses regrow.
