Functional impact of Kir4.1 channels in hippocampal NG2 glia on neuronal plasticity and behavior

Abstract

NG2 glia represents the 4th type of CNS glial cells. In white matter, most of them differentiate into myelinating oligodendrocytes but in grey matter a majority retains their NG2 phenotype throughout life. Intriguingly, these glial cells are the only non-neuronal cell type, receiving direct synaptic input from glutamatergic and GABAergic neurons. However, the functional consequence of this highly temporally and spatially restricted way of communication with neurons is not yet understood. The present study aimed to elucidate the role of grey matter NG2 glia and to reveal whether/how these cells influence brain function. For this purpose, a NG2-CreERT2 knock-in mouse line was generated, enabling the deletion of the prominently expressed K+ channel Kir4.1 specifically in NG2 glia upon tamoxifen administration. In its role as a key determinant of passive membrane properties, hippocampal NG2 glia devoid of Kir4.1 displayed depolarized resting potentials and a drastically increased membrane resistance. These changes promoted the excitability of these knockout cells as revealed by strong and long-lasting responses upon quantal transmitter release at the neuron-NG2 glia-synapse. NG2 glia-targeted deletion of the Kir4.1 gene further entailed an increase of myelin protein transcripts in recombined cells and an upregulation of MBP protein, a main component of myelin sheaths. On neuronal circuit level it could be shown that not only short-term plasticity at the Schaffer collateral - NG2 glia synapse was altered in mice lacking Kir4.1 in NG2 glia, but also long-term potentiation (LTP) at synapses formed between CA3 and CA1 pyramidal neurons. As LTP is considered a cellular basis for learning and memory, the impaired potentiation was expected to be apparent on the behavior level. Surprisingly, animal performance during the novel object location recognition memory task indicated an improved declarative memory of Kir4.1-deficient mice. The functional impact of Kir4.1 deletion on other brain regions still needs to be investigated. First experiments performed in the cerebellum imply a regionally diverse impact of Kir4.1 knockout in NG2 glia. Short term plasticity was unaltered at cerebellar climbing fiber - NG2 glia synapse, in contrast to the situation in the hippocampus. Differentiation of NG2 glia into oligodendrocytes was, however, increased in the cerebellar molecular layer but not in the cerebellar granule cells layer or in the hippocampus. On the behavioral level, mice with a NG2 glia-targeted Kir4.1-deficiency showed improved motor coordination in the beam walk paradigm, a test of cerebellar function. <br /> In summary the findings presented here, provide exciting insights into the ability of NG2 glia to influence neuronal plasticity and animal behavior. The K+ channel Kir4.1 expressed in NG2 glia seems to have a key function in determining NG2 glia excitability and in driving intracellular processes that enable NG2 glia to provoke changes of myelination, neuronal circuit function and memory performance.