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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

GIRK2 Channels in Down Syndrome and Alzheimer’s Disease

Author(s): Alexander Kleschevnikov*

Volume 19, Issue 12, 2022

Published on: 05 January, 2022

Page: [819 - 829] Pages: 11

DOI: 10.2174/1567205020666221223122110

Price: $65


Cognitive impairment in Down syndrome (DS) results from the abnormal expression of hundreds of genes. However, the impact of KCNJ6, a gene located in the middle of the ‘Down syndrome critical region’ of chromosome 21, seems to stand out. KCNJ6 encodes GIRK2 (KIR3.2) subunits of G protein-gated inwardly rectifying potassium channels, which serve as effectors for GABAB, m2, 5HT1A, A1, and many other postsynaptic metabotropic receptors. GIRK2 subunits are heavily expressed in neocortex, cerebellum, and hippocampus. By controlling resting membrane potential and neuronal excitability, GIRK2 channels may thus affect both synaptic plasticity and stability of neural circuits in the brain regions important for learning and memory. Here, we discuss recent experimental data regarding the role of KCNJ6/GIRK2 in neuronal abnormalities and cognitive impairment in models of DS and Alzheimer’s disease (AD). The results compellingly show that signaling through GIRK2 channels is abnormally enhanced in mouse genetic models of Down syndrome and that partial suppression of GIRK2 channels with pharmacological or genetic means can restore synaptic plasticity and improve impaired cognitive functions. On the other hand, signaling through GIRK2 channels is downregulated in AD models, such as models of early amyloidopathy. In these models, reduced GIRK2 channel signaling promotes neuronal hyperactivity, causing excitatory-inhibitory imbalance and neuronal death. Accordingly, activation of GABAB/GIRK2 signaling by GIRK channel activators or GABAB receptor agonists may reduce Aβ-induced hyperactivity and subsequent neuronal death, thereby exerting a neuroprotective effect in models of AD.

Keywords: Down syndrome, Alzheimer’s disease, GIRK2 channels, genetic disorders, neuronal hyperactivity, KCNJ6.

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