Scientists say they have discovered a molecular mechanism that plays a central role in intact long-term memory. This mechanism is also involved in physiological memory loss in old age.

Many life forms, from worms to humans, have differentiated memory functions, such as short-term and long-term memory, according to the researchers, who add that, at the cell and molecule level, many of these functions are nearly identical from life form to life form. Detecting the molecules involved in memory processes is of great importance to both basic and clinical research, since it can point the way to the development of drugs for memory disorders.

The researchers, who study roundworms (Caenorhabditis elegans) at the Transfaculty Research Platform for Molecular and Cognitive Neurosciences (MCN) at the University of Basel, report their findings Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline” in Current Biology.

“Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (Kv) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating Kv channels; however, their possible role in the regulation of memory and age-dependent memory decline are unknown,” write the investigators.

“Here, we show that, in C. elegansmps-2 is the sole member of the MiRP family that controls exclusively long-term associative memory (LTAM) in AVA neuron. In addition, we demonstrate that mps-2 also plays a critical role in age-dependent memory decline. In young adult worms, mps-2 is transcriptionally upregulated by CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) during LTAM, although the mps-2 baseline expression is CREB independent and instead, during aging, relies on nhr-66, which acts as an age-dependent repressor. Deletion of nhr-66 or its binding element in the mps-2 promoter prevents age-dependent transcriptional repression of mps-2 and memory decline.

“Finally, MPS-2 acts through the modulation of the Kv2.1/KVS-3 and Kv2.2/KVS-4 heteromeric potassium channels. Altogether, we describe a conserved MPS-2/KVS-3/KVS-4 pathway essential for LTAM and also for a programmed control of physiological age-dependent memory decline.”

The team led by Attila Stetak, PhD, Andreas Papassotiropoulos, PhD, and Dominique de Quervain, PhD, used sensory stimuli to first examine the learning and memory ability of genetically modified roundworms lacking a certain gene, mps-2. This gene contains the blueprint for part of a voltage-dependent ion channel in the nerve cell membrane and is suspected of playing a role in memory functions.

It was found that modified worms had equally good short-term memory as unmodified specimens. However, as the length of the experiment increased, the researchers found that the genetically modified worms were less able to retain what they learned. Without mps-2, they had a reduced long-term memory.

In roundworms, as in humans, a loss of memory can be observed with increasing age. However, the molecular basis for this process is largely unclear. In further experiments, the researchers were able to prove that unmodified worms with the mps-2 gene exhibit a strong reduction of the MPS-2 protein in old age. This was related to reduced memory performance.

This lack of MPS-2 protein proved not to be a passive but an actively regulated process. The research team was able to identify another protein, NHR-66, as responsible for regulating this deficiency. NHR-66 actively curbs the reading of the mps-2 gene and thus production of the MPS-2 protein in old age. If in older worms MPS-2 protein level was artificially induced or their NHR-66 was turned off, they had a similarly good memory as younger worms.

Both molecules, MPS-2 and NHR-66, make for interesting targets for drugs that could mitigate age-related memory loss, according to the researchers who want to examine therapeutic options based on their discovery.

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