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Published on: March 23, 2011
Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline
Bank G Fenyves1, Andreas Arnold2, Vaibhav G Gharat2
1Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Department of Molecular Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
Abstract:
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. Here, we show that, in C. elegans, mps-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.
Insights
The MPS-2 protein regulates long-term associative memory (LTAM) in C. elegans and prevents age-dependent memory decline by modulating potassium channels. This pathway is crucial for memory formation and healthy aging.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neuronal plasticity underlies learning and memory.
- Voltage-gated potassium (Kv) channels regulate neuronal excitability and may be involved in age-related memory dysfunction.
- MinK-related peptides (MiRPs) modulate Kv channels, but their role in memory is unknown.
Purpose of the Study:
- Investigate the role of MiRPs in long-term associative memory (LTAM) and age-dependent memory decline in C. elegans.
- Identify the specific MiRP family member and its associated molecular pathways involved in memory regulation.
- Elucidate the mechanisms by which MPS-2 influences neuronal function and memory across the lifespan.
Main Methods:
- Utilized C. elegans as a model organism.
- Conducted genetic screens and molecular analyses to identify the mps-2 gene and its regulatory elements.
- Performed behavioral assays to assess LTAM and age-dependent memory.
- Investigated gene expression patterns and protein interactions using transcriptional and post-transcriptional analysis.
- Examined the functional impact of MPS-2 on specific potassium channels (KVS-3 and KVS-4).
Main Results:
- Identified mps-2 as the sole MiRP family member in C. elegans regulating LTAM in AVA neurons.
- Demonstrated that mps-2 plays a critical role in preventing age-dependent memory decline.
- Showed that CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) upregulates mps-2 during LTAM in young worms.
- Revealed that the transcription factor nhr-66 acts as an age-dependent repressor of mps-2 baseline expression.
- Found that deleting nhr-66 or its binding site prevents age-dependent repression of mps-2 and subsequent memory loss.
- Established that MPS-2 modulates Kv2.1/KVS-3 and Kv2.2/KVS-4 heteromeric potassium channels.
Conclusions:
- The MPS-2/KVS-3/KVS-4 pathway is essential for LTAM in C. elegans.
- MPS-2 is a key regulator of physiological age-dependent memory decline.
- Understanding this pathway offers insights into conserved mechanisms of memory maintenance and aging.
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