Biology subjects

Stetak, A.

Publications and source records attributed to Stetak, A..

2 recordsLinked to original sources

bioRxiv2022

A Dual Role for LAR-RPTP in Regulating Long-distance Transport and Synaptic Retention of AMPARs, Essential for Long Term Associative Memory

The AMPA subtype of ionotropic glutamate receptors (AMPARs) plays an essential role in excitatory synaptic transmission, learning, and memory. The majority of AMPARs are made in the cell body and are transported by molecular motors to synapses. Maintaining the proper number of synaptic receptors requires coordinated regulation of receptor production, export from the soma and delivery at synapses. This major logistical process is essential for circuit function and behavior. Although recent studies have shown that long-distance synaptic transport is regulated by neuronal activity, little is known about the mechanisms that coordinate somatic export or synaptic delivery and removal. Here we show that loss of the PTP-3A isoform of the receptor tyrosine phosphatase PTP-3 (the C. elegans homologue of vertebrate LAR-RPTP) leads to a [~]60% decrease in AMPAR transport; this affects synaptic delivery of AMPARs and synaptic functions necessary for long-term associative olfactory memory in C. elegans. Interestingly, while complete loss of PTP-3A leads to defects in transport and local synaptic trafficking of AMPARs, loss of only PTP-3 phosphatase function affects local synaptic recycling and retention of AMPARs. Finally, we show that the N-terminus of PTP-3A regulates transport, whereas the C-terminal regulates synaptic retention of AMPARs. Altogether, our results suggest a model in which the two domains of PTP-3/LAR-RPTPs have specific, complementary roles in coordinating somatic export and local retention of AMPARs essential for long-term associative memory.

neuroscience↗

bioRxiv2022

(-)-Gossypol inhibition of musashi-mediated forgetting improves memory and age-dependent memory decline in Caenorhabditis elegans

Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via a 3UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (-)-gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)-gossypol can regulate the musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of musashi might represent a promising approach for memory modulation.

neuroscience↗