The inherent ability of the neurons in the brain to rewire, reconnect, learn, and store new information with each new experience—called synaptic plasticity—requires the synthesis of new proteins that remodels the hardware of neuronal circuits to encode long-term memories.
Localized protein synthesis at the interfaces of neurons requires a complex relay of messenger RNA from the neuron’s cell body, through extensive microtubular networks in dendritic arms, to synaptic junctions. The transported cargo assembles ribosomes, reads RNA messages, and builds new proteins at the synapses.
A new study published in the journal Cell Reports, “Molecular motor protein KIF5C mediates structural plasticity and long-term memory by constraining local translation” provides new insights on the mechanics underlying synaptic plasticity. The study is funded by the National Institutes of Health, the National Science Foundation and the Lottie French Lewis Fund of the Community Foundation for Palm Beach and Martin Counties, Florida.
New research from the lab of Sathya Puthanveettil, PhD, neuroscientist at Scripps Research, shows that among the network of courier molecules in neurons are two members of the kinesin family, KIF5C and KIF3A. The authors show when KIF5C is removed from specific neurons in the hippocampus in mouse models, their ability to branch out dendrites and form input-receiving spines suffers. An excess of Kif5C protein improves these traits.
Behavioral studies on mouse models show that loss of KIF5C in hippocampal neurons diminishes spatial and fear-associated memory and when present in excess memory is enhanced and amplified.
Supriya Swarnkar, PhD, research associate in the Puthanveettil lab and first author on the paper says discerning the role of Kif motors in synaptic plasticity points to possible causes of neurological disorders, and offers new directions for treatment.
“The ability to form memories depends on the proper functioning of the neuron’s long-distance transport system from cell body to synapse,” says Swarnkar. “And many studies have reported links between mutations in Kifs and neurological disorders, including intellectual disability, autism and ALS.”
Puthanveettil says there are 46 Kif molecular machines, each specialized to carry different types of cargo. Scientists are beginning to identify the cargo of individual Kifs.
By isolating complexes of cargo loaded KIF5C and sequencing the associated RNA, the Puthanveettil team found around 650 different RNAs that depend upon the KIF5C’s courier services. This includes an RNA that provides the code to initiate protein synthesis, called EIF3G. The ability to remodel the synapse with experience and to learn is impaired if EIF3G is not available at synapses, says Puthanveettil.
The team generated mice and cells with an excess and lack of KIF5C and KIF3A to better understand the role of these Kifs in long-term memory storage and recall. The mouse models selective altered the amount of these Kifs in specific neurons called CA1 neurons in the hippocampus—a region of the limbic system of the brain involved in multiple forms of learning, including the consolidation of information from short-term memory to long-term memory, and the encoding of spatial memory.
Over-expressing KIF5C in cells in a dish showed increased synaptic transmission, increased branching of dendritic arms, and an eruption of signal-receiving mushroom spines that are correlated with memory and synaptic plasticity.
The study offers new insights for addressing a wide variety of neuropsychiatric disorders. “Intellectual disability, depression, epilepsy, Alzheimer’s disease – anything that could benefit from greater or lesser expression of key proteins in neurons’ dendrites might respond to a boosting or diminishing these molecular couriers,” says Puthanveettil.