Nature sub-journal: Humans have discovered the first genetic mutation that improves cognitive flexibility.

Author: nagashi people, as the soul of all things, their super cognitive ability makes us get out of the category of animals, understand nature and then transform nature, so that human beings can stand at the top of the food chain.cognitive ability refers to the ability of human brain to process, store and extract information, that is, the ability of human beings to grasp the composition of things, the relationship between performance and other things, the power of development, the direction of development and the basic laws.it is the most important psychological condition for people to complete activities successfully. The abilities of perception, memory, thinking and imagination are all considered as part of cognitive ability.recently, researchers from the National Institute of child health and human development published a research paper entitled activity dependent isomerization of Kv4.2 by Pin1 regulations coherent flexibility in nature communications.this study describes a Pin1 dependent mechanism that regulates the association of Kv4.2, a subtype of potassium channel a, with its accessory subunit ddpp6, thereby altering neuronal excitability and cognitive flexibility.this study may eventually enhance people's understanding of human cognitive flexibility.may also contribute to the understanding of epilepsy, schizophrenia, fragile X syndrome and autism.voltage gated K + channels regulate brain function in macromolecular complexes with accessory subunits.Kv4.2 is a member of the SHA1 family and a type of K + channel that is significantly expressed in the dendrites of hippocampal CA1 pyramidal neurons.in the control of dendritic excitability, Kv4.2 can affect the plasticity of neurons and help learning and memory.Kv4.2 reconstructs the NMDA receptor of synapses by regulating the proportion of NR2B / NR2A subunits in synapses.in addition, abnormal Kv4.2 activity was also associated with ASD, temporal lobe epilepsy and fragile X syndrome.a large number of studies have shown that Kv4.2 channel interacts with K + channel interacting protein (kchip1-4) and dipeptidyl peptidase (DPP6 / 10) in macromolecular protein complexes.DPP6 is a type II transmembrane protein, which can increase the membrane expression and single channel conductance of Kv4.2, and accelerate the inactivation and recovery of Kv4.studies have shown that Kv4.2 mediates an increase in the current density from the cell body to the distal synapse in CA1 hippocampal pyramidal neurons. However, this gradient disappeared in DPP6 knockout mice.more interestingly, DPP6 seems to be able to independently regulate the development of hippocampal synapses in addition to many aspects of Kv4.2 function regulation.recent studies have confirmed that DPP6 and dpp10 are associated with autism, permafrost and neurodegeneration. Therefore, the regulation of kv4.2-dpp6 complex may not only affect the activity of Kv4.2 channel, but also affect the independent function of DPP6. however, little is known about how to regulate the stability or composition of this complex. through tap-ms immunocoprecipitation experiment, the researchers found that Pin1, which interacts with Kv4.2, is a proline isomerase, which can selectively combine with pser / Thr Pro motif and isomerize it. The following biochemical studies also showed that Pin1 was directly bound to Kv4.2 via a typical pser / Thr Pro motif. pser / Thr Pro motifs can exist in cis and trans stereoconformations, while Pin1 can specifically accelerate cis / trans conversion, thus regulating phosphorylated signal transduction. previous studies have shown that Pin1 imbalance plays an important role in many neuropathological States, including Alzheimer's disease, and can prevent age-dependent neurodegeneration. the researchers also found that epilepsy induction and exposure to rich and new environments could increase the phosphorylation of Kv4.2 and Pin1 binding site t607 in mouse cortex and hippocampus through p38 MAPK. using biochemical and electrophysiological techniques, they also found that Pin1 is required for the dissociation of kv4.2-dpp6 complex, which changes the excitability of neurons. to confirm these observations, the researchers constructed a mouse model of Kv4.2 t607a mutation, which eliminated phosphorylation and subsequent isomerization of an important C-terminal Pin1 motif. these mutant mice showed significant phenotypic mimicry effect compared with mice treated with Pin1 inhibitor. more interestingly, Kv4.2 t607a mice showed normal initial learning ability, but improved reverse learning ability in multiple behavioral tasks. here, this study introduces a new mechanism that Pin1 regulates kv4.2-dpp6 complex and affects cognitive flexibility. in conclusion, in this study, the researchers reported a Pin1 dependent mechanism that regulates the composition, neuronal excitability and cognitive flexibility of the kv4.2-dpp6 complex. in addition, t607 is a binding site of Kv4.2 and Pin1, and Kv4.2 t607a mutant mice show stronger ability to reverse learning. paper links: