Unable to carry signals based on sights and sounds to the genes that record memories, a broken shuttle protein may hinder learning in patients with intellectual disability, schizophrenia, and autism. This is the implication of a study led by researchers published in Nature Communications.
Specifically, the research team found that mice genetically engineered to lack the gene for the gamma-CaMKII shuttle protein took twice as long as normal mice to form a memory needed to complete a simple task.
"Our study shows for the first time that gamma-CaMKII plays a critical role in learning and memory in live animals," says the senior author.
"Adding more weight to our results, we showed that making the same change in the shuttle's structure seen in a human child with severe intellectual disability also took away the ability of mice to learn," says the senior author and suggests that the shuttle works similarly in the two species.
The research team then restored the learning ability by re-inserting the human version of the shuttle protein into mice.
The current study revolves around the nerve cells that coordinate thought and memory. Each cell in a nerve pathway sends an electric pulse down its branches until it reaches a synapse, a gap between itself and the next cell in line. Signals that form memories start at synapses where sights and sounds trigger responses, and end when genes are turned on in the nuclei of nerve cells to make permanent, physical changes in their connections.
When sensory information triggers known mechanisms near synapses, calcium is released into nerve cells, building up until it triggers chain reactions fine-tuned by partnering proteins like calmodulin or CaM, say the study authors. When calcium and CaM link up and arrive in a nerve cell's nucleus, the compartment where genes operate, they set off reactions known to activate the protein CREB, which dials up the action of genes previously linked to memory formation.
Going into the study, a "missing link" in the field was an understanding of how synapses "talk to" nerve cell nuclei as memories form. In the current study, researchers determined for the first time that this communication occurs when gamma-CaMKII shuttles the calcium/calmodulin complexes that form just inside of nerve cells to their nuclei.
Comparing spatial memory in mice without gamma-CaMKII to normal mice, the study authors found that gamma-CaMKII "knockout" mice were much less able to locate a platform hidden beneath the surface of murky water in a maze. During this exercise, normal mice quickly identify the platform's location.
The team also found that, an hour after maze training, normal mice displayed a significant increase in expression of three genes--BDNF, c-Fos, and Arc--known from past studies to help form long-term, spatial memories based on experiences. In contrast, training-induced increases in the expression of these genes did not occur in mice engineered to lack gamma-CaMKII.
Along with removing the entire gene encoding gamma-CaMKII protein from some mice, a separate group of mice were engineered to have a version of the protein with a small change found by a 2012 study in a boy with severe intellectual disability. In the nerve cells of the boy, the protein building block at position 292 in the amino acid backbone of gamma-CaMKII, typically arginine, was occupied instead by a proline residue (R292P). The change rendered this protein a thousand times less able to trap the calcium-calmodulin complex, so it often arrived in nerve cell nuclei without its cargo.
https://nyulangone.org/press-releases/broken-shuttle-may-hinder-learning-across-several-brain-disorders
https://www.nature.com/articles/s41467-018-04705-8
Latest News
The assembly of the human c…
By newseditor
Posted 24 Apr
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
Other Top Stories
New HIV vaccine target!
Read more
Twin study finds that gut microbiomes run in families
Read more
Genetically engineered world's first Zika virus infectious cDNA clone!
Read more
How antibodies access neurons to fight infection
Read more
Why humans (and not mice) are susceptible to Zika
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Integrative spatial analysi…
By newseditor
Posted 24 Apr
Time-series reconstruction…
By newseditor
Posted 24 Apr
Harnessing gastrointestinal…
By newseditor
Posted 24 Apr
Sex-specific modulation of…
By newseditor
Posted 24 Apr
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar