Adelman, J.P., 2016. SK channels and calmodulin. Channels 10, 1–6. https://doi.org/
10.1080/19336950.2015.1029688.
Adelman, J.P., Maylie, J., Sah, P., 2012. Small-conductance Ca2+-activated K+
channels: form and function. Annu. Rev. Physiol. 74, 245–269. https://doi.org/
10.1146/annurev-physiol-020911-153336.
Aguzzi, A., Barres, B.A., Bennett, M.L., 2013. Microglia: scapegoat, saboteur, or
something else? Science 339, 156–161. https://doi.org/10.1126/science.1227901.
Ashwell, K., 1990. Microglia and cell death in the developing mouse cerebellum. Dev.
Brain Res. 55, 219–230. https://doi.org/10.1016/0165-3806(90)90203-b.
Ayata, P., Badimon, A., Strasburger, H.J., Duff, M.K., Montgomery, S.E., Loh, Y.E.,
Ebert, A., Pimenova, A.A., Ramirez, B.R., Chan, A.T., Sullivan, J.M.,
Purushothaman, I., Scarpa, J.R., Goate, A.M., Busslinger, M., Shen, L., Losic, B.,
Schaefer, A., 2018. Epigenetic regulation of brain region-specific microglia clearance
activity. Nat. Neurosci. 21, 1049–1060. https://doi.org/10.1038/s41593-018-01923.
Barichello, T., Sayana, P., Giridharan, V.V., Arumanayagam, A.S., Narendran, B.,
Giustina, A.D., Petronilho, F., Quevedo, J., Dal-Pizzol, F., 2019. Long-term cognitive
outcomes after sepsis: a translational systematic review. Mol. Neurobiol. 56,
186–251. https://doi.org/10.1007/s12035-018-1048-2.
Beattie, E.C., Stellwagen, D., Morishita, W., Bresnahan, J.C., Ha, B.K., Von Zastrow, M.,
Beattie, M.S., Malenka, R.C., 2002. Control of synaptic strength by glial TNFalpha.
Science 295, 2282–2285. https://doi.org/10.1126/science.1067859.
Belmeguenai, A., Hosy, E., Bengtsson, F., Pedroarena, C.M., Piochon, C., Teuling, E.,
He, Q., Ohtsuki, G., De Jeu, M.T., Elgersma, Y., De Zeeuw, C.I., J¨
orntell, H.,
Hansel, C., 2010. Intrinsic plasticity complements long-term potentiation in parallel
fiber input gain control in cerebellar Purkinje cells. J. Neurosci. 30, 13630–13643.
https://doi.org/10.1523/JNEUROSCI.3226-10.2010.
Bienenstock, E.L., Cooper, L.N., Munro, P.W., 1982. Theory for the development of
neuron selectivity: orientation specificity and binocular interaction in visual cortex.
J. Neurosci. 2, 32–48. https://doi.org/10.1523/JNEUROSCI.02-01-00032.1982.
Bock, T., Stuart, G.J., 2016. The impact of BK channels on cellular excitability depends
on their subcellular location. Front. Cell. Neurosci. 10, 206. https://doi.org/
10.3389/fncel.2016.00206.
Bock, T., Honnuraiah, S., Stuart, G.J., 2019. Paradoxical excitatory impact of SK channels
on dendritic excitability. J. Neurosci. 39, 7826–7839. https://doi.org/10.1523/
JNEUROSCI.0105-19.2019.
Breton, J.D., Stuart, G.J., 2009. Loss of sensory input increases the intrinsic excitability of
layer 5 pyramidal neurons in rat barrel cortex. J. Physiol. 587, 5107–5119. https://
doi.org/10.1113/jphysiol.2009.180943.
5. Conclusions
Our study shows that the directionality of the microglia-triggered
intrinsic plasticity is inverted between the mPFC L5 pyramidal cells
and the cerebellar Purkinje cells. The induction of the hypoexcitability
plasticity of mPFC L5 pyramidal neurons is mediated by the TNF- α and
is dependent on the intraneuronal activity of protein phosphatases. The
functional upregulation of SK1 channels is involved in the LTD of mPFC
pyramidal cells. The contrasting responses against acute inflammation
in the two brain regions may cause the impairment of network func
tional connectivity during immune-associated brain dysfunctions.
Animal ethics statement
All procedures were performed following the guidelines of the Ani
mal Care and Use Committees and approved by the Ethical Committee of
Kyoto University. All animal handling and reporting comply with the
ARRIVE guidelines. Rats were housed (5 animals at maximum in each
cage) and maintained under a 12-h light: 12-h dark cycle, at a constant
temperature and humidity (20–24 ◦ C, 35%–55%), with food and water
available ad libitum.
Funding sources
This work was supported by grants from the Brain Science
14
Y. Yamawaki et al.
Current Research in Neurobiology 3 (2022) 100028
Campanac, E., Daoudal, G., Ankri, N., Debanne, D., 2008. Downregulation of dendritic I
(h) in CA1 pyramidal neurons after LTP. J. Neurosci. 28, 8635–8643. https://doi.
org/10.1523/JNEUROSCI.1411-08.2008.
Carta, I., Chen, C.H., Schott, A.L., Dorizan, S., Khodakhah, K., 2019. Cerebellar
modulation of the reward circuitry and social behavior. Science 363, 1–10. https://
doi.org/10.1126/science.aav0581.
Chen, S., Benninger, F., Yaari, Y., 2014. Role of small conductance Ca2⁺-activated K⁺
channels in controlling CA1 pyramidal cell excitability. J. Neurosci. 34, 8219–8230.
https://doi.org/10.1523/JNEUROSCI.0936-14.2014.
Chetkovich, D.M., Chen, L., Stocker, T.J., Nicoll, R.A., Bredt, D.S., 2002. Phosphorylation
of the postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 binding site of
stargazin regulates binding to PSD-95 and synaptic targeting of AMPA receptors.
J. Neurosci. 22, 5791–5796. https://doi.org/10.1523/JNEUROSCI.22-1405791.2002.
Chitu, V., Gokhan, S¸., Nandi, S., Mehler, M.F., Stanley, E.R., 2016. Emerging roles for
CSF-1 receptor and its ligands in the nervous system. Trends Neurosci. 39, 378–393.
https://doi.org/10.1016/j.tins.2016.03.005.
Chung, W.S., Welsh, C.A., Barres, B.A., Stevens, B., 2015. Do glia drive synaptic and
cognitive impairment in disease? Nat. Neurosci. 18, 1539–1545. https://doi.org/
10.1038/nn.4142.
Coesmans, M., Weber, J.T., De Zeeuw, C.I., Hansel, C., 2004. Bidirectional parallel fiber
plasticity in the cerebellum under climbing fiber control. Neuron 44, 691–700.
https://doi.org/10.1016/j.neuron.2004.10.031.
Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M.
W., De Koninck, Y., 2005. BDNF from microglia causes the shift in neuronal anion
gradient underlying neuropathic pain. Nature 438, 1017–1021. https://doi.org/
10.1038/nature04223.
Daoudal, G., Debanne, D., 2003. Long-term plasticity of intrinsic excitability: learning
rules and mechanisms. Learn. Mem. 10, 456–465. https://doi.org/10.1101/
lm.64103.
Daoudal, G., Hanada, Y., Debanne, D., 2002. Bidirectional plasticity of excitatory
postsynaptic potential (EPSP)-spike coupling in CA1 hippocampal pyramidal
neurons. Proc. Natl. Acad. Sci. U. S. A. 99, 14512–14517. https://doi.org/10.1073/
pnas.222546399.
Davalos, D., Ryu, J.K., Merlini, M., Baeten, K.M., Le Moan, N., Petersen, M.A.,
Deerinck, T.J., Smirnoff, D.S., Bedard, C., Hakozaki, H., Gonias Murray, S., Ling, J.
B., Lassmann, H., Degen, J.L., Ellisman, M.H., Akassoglou, K., 2012. Fibrinogeninduced perivascular microglial clustering is required for the development of axonal
damage in neuroinflammation. Nat. Commun. 3, 1227. https://doi.org/10.1038/
ncomms2230.
De Biase, L.M., Schuebel, K.E., Fusfeld, Z.H., Jair, K., Hawes, I.A., Cimbro, R., Zhang, H.Y., Liu, Q.-R., Shen, H., Xi, Z.-X., Goldman, D., Bonci, A., 2017. Local cues establish
and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95,
341–356. https://doi.org/10.1016/j.neuron.2017.06.020 e6.
Desai, N.S., Rutherford, L.C., Turrigiano, G.G., 1999. Plasticity in the intrinsic
excitability of cortical pyramidal neurons. Nat. Neurosci. 2, 515–520. https://doi.
org/10.1038/9165.
Duan, L., Zhang, X.D., Miao, W.Y., Sun, Y.J., Xiong, G., Wu, Q., Li, G., Yang, P., Yu, H.,
Li, H., Wang, Y., Zhang, M., Hu, L.Y., Tong, X., Zhou, W.H., Yu, X., 2018. PDGFRβ
cells rapidly relay inflammatory signal from the circulatory system to neurons via
chemokine CCL2. Neuron 100, 183–200. https://doi.org/10.1016/j.
neuron.2018.08.030 e8.
Ehlers, M.D., 2000. Reinsertion or degradation of AMPA receptors determined by
activity-dependent endocytic sorting. Neuron 28, 511–525. https://doi.org/
10.1016/s0896-6273(00)00129-x.
Elmore, M.R., Najafi, A.R., Koike, M.A., Dagher, N.N., Spangenberg, E.E., Rice, R.A.,
Kitazawa, M., Matusow, B., Nguyen, H., West, B.L., Green, K.N., 2014. Colonystimulating factor 1 receptor signaling is necessary for microglia viability,
unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397.
https://doi.org/10.1016/j.neuron.2014.02.040.
Feldman, D.E., Brecht, M., 2005. Map plasticity in somatosensory cortex. Science 310,
810–815. https://doi.org/10.1126/science.1115807.
Fern´
andez-Fern´
andez, D., Lamas, J.A., 2021. Metabotropic modulation of potassium
channels during synaptic plasticity. Neuroscience 456, 4–16. https://doi.org/
10.1016/j.neuroscience.2020.02.025.
Gao, F., Liu, Z., Ren, W., Jiang, W., 2014. Acute lipopolysaccharide exposure facilitates
epileptiform activity via enhanced excitatory synaptic transmission and neuronal
excitability in vitro. Neuropsychiatric Dis. Treat. 10, 1489–1495. https://doi.org/
10.2147/NDT.S65695.
Gill, D.F., Hansel, C., 2020. Muscarinic modulation of SK2-type K + channels promotes
intrinsic plasticity in L2/3 pyramidal neurons of the mouse primary somatosensory
cortex. eNeuro 7. https://doi.org/10.1523/ENEURO.0453-19.2020. ENEURO.045319.2020.
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F.,
Conway, S.J., Ng, L.G., Stanley, E.R., Samokhvalov, I.M., Merad, M., 2010. Fate
mapping analysis reveals that adult microglia derive from primitive macrophages.
Science 330, 841–845. https://doi.org/10.1126/science.1194637.
Grabert, K., Michoel, T., Karavolos, M.H., Clohisey, S., Baillie, J.K., Stevens, M.P.,
Freeman, T.C., Summers, K.M., McColl, B.W., 2016. Microglial brain regiondependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19,
504–516. https://doi.org/10.1038/nn.4222.
Granja, M.G., Alves, L.P., Leardini-Trist˜
ao, M., Bortoni, L.C., Saul, M.E., de Moraes, F.M.,
Ferreira, E.C., de Moraes, B.P.T., da Silva, V.Z., dos Santos, A.F.R., Silva, A.R.,
Gonçalves-de-Albuquerque, C.F., Bambini-Junior, V., Weyrich, A.S., Rondina, M.T.,
Zimmerman, G.A., de Castro-Faria-Neto, H.C., 2021. Inflammatory, synaptic, motor
and behavioral alterations induced by gestational sepsis on the offspring at different
stages of life. J. Neuroinflammation 18, 60. https://doi.org/10.1186/s12974-02102106-1.
Grasselli, G., He, Q., Wan, V., Adelman, J.P., Ohtsuki, G., Hansel, C., 2016. Activitydependent plasticity of spike pauses in cerebellar Purkinje cells. Cell Rep. 14,
2546–2553. https://doi.org/10.1016/j.celrep.2016.02.054.
Grasselli, G., Boele, H., Titley, H.K., Bradford, N., van Beers, L., Jay, L., Beekhof, G.C.,
Busch, S.E., De Zeeuw, C.I., Schonewille, M., Hansel, C., 2020. SK2 channels in
cerebellar Purkinje cells contribute to excitability modulation in motor-learningspecific memory traces. PLoS Biol. 18, e3000596 https://doi.org/10.1371/journal.
pbio.3000596.
Gu, N., Hu, H., Vervaeke, K., Storm, J.F., 2008. SK (KCa2) channels do not control
somatic excitability in CA1 pyramidal neurons but can be activated by dendritic
excitatory synapses and regulate their impact. J. Neurophysiol. 100, 2589–2604.
https://doi.org/10.1152/jn.90433.2008.
Habbas, S., Santello, M., Becker, D., Stubbe, H., Zappia, G., Liaudet, N., Klaus, F.R.,
Kollias, G., Fontana, A., Pryce, C.R., Suter, T., Volterra, A., 2015. Neuroinflammatory
TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741. https://doi.org/
10.1016/j.cell.2015.11.023.
Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N., Audinat, E., 2012. Deficiency of
the microglial receptor CX3CR1 impairs postnatal functional development of
thalamocortical synapses in the barrel cortex. J. Neurosci. 32, 15106–15111.
https://doi.org/10.1523/JNEUROSCI.1167-12.2012.
Hull, C.A., Chu, Y., Thanawala, M., Regehr, W.G., 2013. Hyperpolarization induces
along-term increase in the spontaneous firing rate of cerebellar Golgi cells.
J. Neurosci. 33, 5895–5902. https://doi.org/10.1523/jneurosci.4052-12.2013.
Ito, M., 1957. The electrical activity of spinal ganglion cells investigated with
intracellular microelectrodes. Jpn. J. Physiol. 7, 297–323. https://doi.org/10.2170/
jjphysiol.7.297.
J¨
orntell, H., Hansel, C., 2006. Synaptic memories upside down: bidirectional plasticity at
cerebellar parallel fiber-Purkinje cell synapses. Neuron 52, 227–238. https://doi.
org/10.1016/j.neuron.2006.09.032.
Jung, H.Y., Staff, N.P., Spruston, N., 2001. Action potential bursting in subicular
pyramidal neurons is driven by a calcium tail current. J. Neurosci. 21, 3312–3321.
https://doi.org/10.1523/JNEUROSCI.21-10-03312.2001.
Kelly, R.M., Strick, P.L., 2003. Cerebellar loops with motor cortex and prefrontal cortex
of a nonhuman primate. J. Neurosci. 23, 8432–8444. https://doi.org/10.1523/
JNEUROSCI.23-23-08432.2003.
Kelly, E., Meng, F., Fujita, H., Morgado, F., Kazemi, Y., Rice, L.C., Ren, C., Escamilla, C.
O., Gibson, J.M., Sajadi, S., Pendry, R.J., Tan, T., Ellegood, J., Basson, M.A.,
Blakely, R.D., Dindot, S.V., Golzio, C., Hahn, M.K., Katsanis, N., Robins, D.M.,
Silverman, J.L., Singh, K.K., Wevrick, R., Taylor, M.J., Hammill, C., Anagnostou, E.,
Pfeiffer, B.E., Stoodley, C.J., Lerch, J.P., Du Lac, S., Tsai, P.T., 2020. Regulation of
autism-relevant behaviors by cerebellar–prefrontal cortical circuits. Nat. Neurosci.
23, 1102–1110. https://doi.org/10.1038/s41593-020-0665-z.
Khandaker, G.M., Cousins, L., Deakin, J., Lennox, B.R., Yolken, R., Jones, P.B., 2015.
Inflammation and immunity in schizophrenia: implications for pathophysiology and
treatment. Lancet Psychiatr. 2, 258–270. https://doi.org/10.1016/S2215-0366(14)
00122-9.
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E.G.,
Wieghofer, P., Heinrich, A., Riemke, P., H¨
olscher, C., Müller, D.N., Luckow, B.,
Brocker, T., Debowski, K., Fritz, G., Opdenakker, G., Diefenbach, A., Biber, K.,
Heikenwalder, M., Geissmann, F., Rosenbauer, F., Prinz, M., 2013. Microglia emerge
from erythromyeloid precursors via Pu.1-and Irf8- dependent pathways. Nat.
Neurosci. 16, 273–280. https://doi.org/10.1038/nn.3318.
Klapal, L., Igelhorst, B.A., Dietzel-Meyer, I.D., 2016. Changes in neuronal excitability by
activated microglia: differential Na(+) current upregulation in pyramid-shaped and
bipolar neurons by TNF-α and IL-18. Front. Neurol. 7, 44. https://doi.org/10.3389/
fneur.2016.00044.
Lawson, L.J., Perry, V.H., Dri, P., Gordon, S., 1990. Heterogeneity in the distribution and
morphology of microglia in the normal adult mouse brain. Neuroscience 39,
151–170. https://doi.org/10.1016/0306-4522(90)90229-w.
LeMessurier, A.M., Feldman, D.E., 2018. Plasticity of population coding in primary
sensory cortex. Curr. Opin. Neurobiol. 53, 50–56. https://doi.org/10.1016/j.
conb.2018.04.029.
Luo, H., Liu, H.Z., Zhang, W.W., Matsuda, M., Lv, N., Chen, G., Xu, Z.Z., Zhang, Y.Q.,
2019. Interleukin-17 regulates neuron-glial communications, synaptic transmission,
and neuropathic pain after chemotherapy. Cell Rep. 29, 2384–2397. https://doi.org/
10.1016/j.celrep.2019.10.085 e5.
Mahon, S., Charpier, S., 2012. Bidirectional plasticity of intrinsic excitability controls
sensory inputs efficiency in layer 5 barrel cortex neurons in vivo. J. Neurosci. 32,
11377–11389. https://doi.org/10.1523/JNEUROSCI.0415-12.2012.
Masi, A., Quintana, D.S., Glozier, N., Lloyd, A.R., Hickie, I.B., Guastella, A.J., 2015.
Cytokine aberrations in autism spectrum disorder: a systematic review and metaanalysis. Mol. Psychiatr. 20, 440–446. https://doi.org/10.1038/mp.2014.59.
Matcovitch-Natan, O., Winter, D.R., Giladi, A., Vargas Aguilar, S., Spinrad, A.,
Sarrazin, S., Ben-Yehuda, H., David, E., Zelada Gonz´
alez, F., Perrin, P., KerenShaul, H., Gury, M., Lara-Astaiso, D., Thaiss, C.A., Cohen, M., Bahar Halpern, K.,
Baruch, K., Deczkowska, A., Lorenzo-Vivas, E., Itzkovitz, S., Elinav, E., Sieweke, M.
H., Schwartz, M., Amit, I., 2016. Microglia development follows a stepwise program
to regulate brain homeostasis. Science 353, aad8670. https://doi.org/10.1126/
science.aad8670.
Matta, S.M., Hill-Yardin, E.L., Crack, P.J., 2019. The influence of neuroinflammation in
autism spectrum disorder. Brain Behav. Immun. 79, 75–90. https://doi.org/
10.1016/j.bbi.2019.04.037.
Mitoma, H., Adhikari, K., Aeschlimann, D., Chattopadhyay, P., Hadjivassiliou, M.,
Hampe, C.S., Honnorat, J., Joubert, B., Kakei, S., Lee, J., Manto, M., Matsunaga, A.,
15
Y. Yamawaki et al.
Current Research in Neurobiology 3 (2022) 100028
Mizusawa, H., Nanri, K., Shanmugarajah, P., Yoneda, M., Yuki, N., 2016. Consensus
paper: neuroimmune mechanisms of cerebellar ataxias. Cerebellum 15, 213–232.
https://doi.org/10.1007/s12311-015-0664-x.
Nandi, S., Gokhan, S., Dai, X.-M., Wei, S., Enikolopov, G., Lin, H., Mehler, M.F.,
Stanley, E.R., 2012. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct
developmental brain expression patterns and regulate neural progenitor cell
maintenance and maturation. Dev. Biol. 367, 100–113. https://doi.org/10.1016/j.
ydbio.2012.03.026.
Nelson, A.B., Krispel, C.M., Sekirnjak, C., du Lac, S., 2003. Long-lasting increases in
intrinsic excitability triggered by inhibition. Neuron 40, 609–620. https://doi.org/
10.1016/S0896-6273(03)00641-X.
Nelson, A.B., Gittis, A.H., du Lac, S., 2005. Decreases in CaMKII activity trigger persistent
potentiation of intrinsic excitability in spontaneously firing vestibular nucleus
neurons. Neuron 46, 623–631. https://doi.org/10.1016/j.neuron.2005.04.009.
Nie, X., Kitaoka, S., Tanaka, K., Segi-Nishida, E., Imoto, Y., Ogawa, A., Nakano, F.,
Tomohiro, A., Nakayama, K., Taniguchi, M., Mimori-Kiyosue, Y., Kakizuka, A.,
Narumiya, S., Furuyashiki, T., 2018. The innate immune receptors TLR2/4 mediate
repeated social defeat stress-induced social avoidance through prefrontal microglial
activation. Neuron 99, 464–479. https://doi.org/10.1016/j.neuron.2018.06.035.
Ohno, H., Kubo, K., Murooka, H., Kobayashi, Y., Nishitoba, T., Shibuya, M., Yoneda, T.,
Isoe, T., 2006. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast
differentiation and osteolytic bone destruction in a bone metastasis model. Mol.
Cancer Therapeut. 5, 2634–2643. https://doi.org/10.1158/1535-7163.MCT-050313.
Ohtsuki, G., 2020. Modification of synaptic-input clustering by intrinsic excitability
plasticity on cerebellar Purkinje cell dendrites. J. Neurosci. 40, 267–282. https://doi.
org/10.1523/JNEUROSCI.3211-18.2019.
Ohtsuki, G., Hansel, C., 2018. Synaptic potential and plasticity of an SK2 channel gate
regulate spike burst activity in cerebellar Purkinje cells. iScience 1, 49–54. https://
doi.org/10.1016/j.isci.2018.02.001.
Ohtsuki, G., Piochon, C., Hansel, C., 2009. Climbing fiber signaling and cerebellar gain
control. Front. Cell. Neurosci. 3, 4. https://doi.org/10.3389/neuro.03.004.2009.
Ohtsuki, G., Piochon, C., Adelman, J.P., Hansel, C., 2012. SK2 channel modulation
contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells.
Neuron 75, 108–120. https://doi.org/10.1016/j.neuron.2012.05.025.
Ohtsuki, G., Shishikura, M., Ozaki, A., 2020. Synergistic excitability plasticity in
cerebellar functioning. FEBS J. 287, 4557–4593. https://doi.org/10.1111/
febs.15355.
Onore, C.E., Careaga, M., Babineau, B.A., Schwartzer, J.J., Berman, R.F., Ashwood, P.,
2013. Inflammatory macrophage phenotype in BTBR T+tf/J mice. Front. Neurosci.
7, 158. https://doi.org/10.3389/fnins.2013.00158.
Ozaki, A., Yamawaki, Y., Ohtsuki, G., 2021. Psychosis symptoms following aberrant
immunity in the brain. Neural Regen Res 16, 512–513. https://doi.org/10.4103/
1673-5374.293148.
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P.,
Giustetto, M., Ferreira, T.A., Guiducci, E., Dumas, L., Ragozzino, D., Gross, C.T.,
2011. Synaptic pruning by microglia is necessary for normal brain development.
Science 333, 1456–1458. https://doi.org/10.1126/science.1202529.
Pape, K., Tamouza, R., Leboyer, M., Zipp, F., 2019. Immunoneuropsychiatry - novel
perspectives on brain disorders. Nat. Rev. Neurol. 15, 317–328. https://doi.org/
10.1038/s41582-019-0174-4.
Park, M.R., Kita, H., Klee, M.R., Oomura, Y., 1983. Bridge balance in intracellular
recording; introduction of the phase-sensitive method. J. Neurosci. Methods 8,
105–125. https://doi.org/10.1016/0165-0270(83)90112-7.
Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates 3rd, J.R., Lafaille, J.J.,
Hempstead, B.L., Littman, D.R., Gan, W.B., 2013. Microglia promote learningdependent synapse formation through brain-derived neurotrophic factor. Cell 155,
1596–1609. https://doi.org/10.1016/j.cell.2013.11.030.
Pascual, O., Ben Achour, S., Rostaing, P., Triller, A., Bessis, A., 2012. Microglia activation
triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc. Natl.
Acad. Sci. U.S.A. 109, E197–E205. https://doi.org/10.1073/pnas.1111098109.
Pribiag, H., Stellwagen, D., 2013. TNF-α downregulates inhibitory neurotransmission
through protein phosphatase 1-dependent trafficking of GABA(A) receptors.
J. Neurosci. 33, 15879–15893. https://doi.org/10.1523/JNEUROSCI.0530-13.2013.
Radnikow, G., Feldmeyer, D., 2018. Layer- and cell type-specific modulation of
excitatory neuronal activity in the neocortex. Front. Neuroanat. 12, 1. https://doi.
org/10.3389/fnana.2018.00001.
Sailer, C.A., Hu, H., Kaufmann, W.A., Trieb, M., Schwarzer, C., Storm, J.F., Knaus, H.G.,
2002. Regional differences in distribution and functional expression of smallconductance Ca2+-activated K+ channels in rat brain. J. Neurosci. 22, 9698–9707.
https://doi.org/10.1523/JNEUROSCI.22-22-09698.2002.
Santello, M., Bezzi, P., Volterra, A., 2011. TNFα controls glutamatergic gliotransmission
in the hippocampal dentate gyrus. Neuron 69, 988–1001. https://doi.org/10.1016/j.
neuron.2011.02.003.
Schafer, D.P., Lehrman, E.K., Kautzman, A.G., Koyama, R., Mardinly, A.R., Yamasaki, R.,
Ransohoff, R.M., Greenberg, M.E., Barres, B.A., Stevens, B., 2012. Microglia sculpt
postnatal neural circuits in an activity and complement-dependent manner. Neuron
74, 691–705. https://doi.org/10.1016/j.neuron.2012.03.026.
Schonewille, M., Belmeguenai, A., Koekkoek, S.K., Houtman, S.H., Boele, H.J., van
Beugen, B.J., Gao, Z., Badura, A., Ohtsuki, G., Amerika, W.E., Hosy, E., Hoebeek, F.
E., Elgersma, Y., Hansel, C., De Zeeuw, C.I., 2010. Purkinje cell-specific knockout of
the protein phosphatase PP2B impairs potentiation and cerebellar motor learning.
Neuron 67, 618–628. https://doi.org/10.1016/j.neuron.2010.07.009.
Schreurs, B.G., Sanchez-Andres, J.V., Alkon, D.L., 1991. Learning-specific differences in
Purkinje-cell dendrites of lobule HVI (Lobulus simplex): intracellular recording in a
rabbit cerebellar slice. Brain Res. 548, 18–22. https://doi.org/10.1016/0006-8993
(91)91100-F.
Segawa, K., Blumenthal, Y., Yamawaki, Y., Ohtsuki, G., 2021. A destruction model of the
vascular and lymphatic systems in the emergence of psychiatric symptoms. Biology
10, 34. https://doi.org/10.3390/biology10010034.
Shih, E.K., Sekerkov´
a, G., Ohtsuki, G., Aldinger, K.A., Chizhikov, V.V., Hansel, C.,
Mugnaini, E., Millen, K.J., 2015. The spontaneous ataxic mouse mutant tippy is
characterized by a novel Purkinje cell morphogenesis and degeneration phenotype.
Cerebellum 14, 292–307. https://doi.org/10.1007/s12311-014-0640-x.
Shim, H.G., Jang, D.C., Lee, J., Chung, G., Lee, S., Kim, Y.G., Jeon, D.E., Kim, S.J., 2017.
Long-term depression of intrinsic excitability accompanied by synaptic depression in
cerebellar Purkinje cells. J. Neurosci. 37, 5659–5669. https://doi.org/10.1523/
JNEUROSCI.3464-16.2017.
Silvin, A., Ginhoux, F., 2018. Microglia heterogeneity along a spatio–temporal axis: more
questions than answers. Glia 66, 2045–2057. https://doi.org/10.1002/glia.23458.
` Kelly, E.A., Lamantia, C.E., Majewska, A.K.,
Sipe, G.O., Lowery, R.L., Tremblay, M.-E.,
2016. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex.
Nat. Commun. 7, 1–10. https://doi.org/10.1038/ncomms10905.
Stevens, B., Allen, N.J., Vazquez, L.E., Howell, G.R., Christopherson, K.S., Nouri, N.,
Micheva, K.D., Mehalow, A.K., Huberman, A.D., Stafford, B., Sher, A., Litke, A.M.,
Lambris, J.D., Smith, S.J., John, W.S., Barres, B.A., 2007. The classical complement
cascade mediates CNS synapse elimination. Cell 131, 1164–1178. https://doi.org/
10.1016/j.cell.2007.10.036.
Stocker, M., 2004. Ca(2+)-activated K+ channels: molecular determinants and function
of the SK family. Nat. Rev. Neurosci. 5, 758–770. https://doi.org/10.1038/nrn1516.
Stocker, M., Hirzel, K., D’hoedt, D., Pedarzani, P., 2004. Matching molecules to function:
neuronal Ca2+-activated K+ channels and afterhyperpolarizations. Toxicon 43,
933–949. https://doi.org/10.1016/j.toxicon.2003.12.009.
Stoessel, M.B., Majewska, A.K., 2021. Little cells of the little brain: microglia in
cerebellar development and function. Trends Neurosci. 44, 564–578. https://doi.
org/10.1016/j.tins.2021.04.001.
Stoodley, C.J., D’Mello, A.M., Ellegood, J., Jakkamsetti, V., Liu, P., Nebel, M.B.,
Gibson, J.M., Kelly, E., Meng, F., Cano, C.A., Pascual, J.M., Mostofsky, S.H., Lerch, J.
P., Tsai, P.T., 2017. Altered cerebellar connectivity in autism and cerebellarmediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751.
https://doi.org/10.1038/s41593-017-0004-1.
Stowell, R.D., Wong, E.L., Batchelor, H.N., Mendes, M.S., Lamantia, C.E., Whitelaw, B.S.,
Majewska, A.K., 2018. Cerebellar microglia are dynamically unique and survey
Purkinje neurons in vivo. Dev Neurobiol 78, 627–644. https://doi.org/10.1002/
dneu.22572.
Stowell, R.D., Sipe, G.O., Dawes, R.P., Batchelor, H.N., Lordy, K.A., Whitelaw, B.S.,
Stoessel, M.B., Bidlack, J.M., Brown, E., Sur, M., Majewska, A.K., 2019.
Noradrenergic signaling in wakeful states inhibits microglial surveillance and
synaptic plasticity in the mouse visual cortex. Nat. Neurosci. 22, 1782–1792.
https://doi.org/10.1038/s41593-019-0514-0.
Suzuki, L., Coulon, P., Sabel-Goedknegt, E.H., Ruigrok, T.J., 2012. Organization of
cerebral projections to identified cerebellar zones in the posterior cerebellum of the
rat. J. Neurosci. 32, 10854–10869. https://doi.org/10.1523/JNEUROSCI.085712.2012.
Süß, P., Hoffmann, A., Rothe, T., Ouyang, Z., Baum, W., Staszewski, O., Schett, G.,
Prinz, M., Kr¨
onke, G., Glass, C.K., Winkler, J., Schlachetzki, J.C.M., 2020. Chronic
peripheral inflammation causes a region-specific myeloid response in the central
nervous system. Cell Rep. 30, 4082–4095. https://doi.org/10.1016/j.
celrep.2020.02.109 e6.
Tanaka, K., Khiroug, L., Santamaria, F., Doi, T., Ogasawara, H., Ellis-Davies, G.C.R.,
Kawato, M., Augustine, G.J., 2007. Ca2+ requirements for cerebellar long-term
synaptic depression: role for a postsynaptic leaky integrator. Neuron 54, 787–800.
https://doi.org/10.1016/j.neuron.2007.05.014.
Tay, T.L., Mai, D., Dautzenberg, J., Fern´
andez-Klett, F., Lin, G., Sagar Datta, M.,
Drougard, A., Stempfl, T., Ardura-Fabregat, A., Staszewski, O., Margineanu, A.,
Sporbert, A., Steinmetz, L.M., Pospisilik, J.A., Jung, S., Priller, J., Grün, D.,
Ronneberger, O., Prinz, M., 2017. A new fate mapping system reveals contextdependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803.
https://doi.org/10.1038/nn.4547.
Titley, H.K., Watkins, G.V., Lin, C., Weiss, C., McCarthy, M., Disterhoft, J.F., Hansel, C.,
2020. Intrinsic excitability increase in cerebellar Purkinje cells after delay eye-blink
conditioning in mice. J. Neurosci. 40, 2038–2046. https://doi.org/10.1523/
JNEUROSCI.2259-19.2019.
Turrigiano, G., Abbott, L.F., Marder, E., 1994. Activity-dependent changes in the intrinsic
properties of cultured neurons. Science 264, 974–977. https://doi.org/10.1126/
science.8178157.
Tzour, A., Leibovich, H., Barkai, O., Biala, Y., Lev, S., Yaari, Y., Binshtok, A.M., 2017. KV
7/M channels as targets for lipopolysaccharide-induced inflammatory neuronal
hyperexcitability. J. Physiol. 595, 713–738. https://doi.org/10.1113/JP272547.
Vaaga, C.E., Brown, S.T., Raman, I.M., 2020. Cerebellar modulation of synaptic input to
freezing-related neurons in the periaqueductal gray. Elife 9, 1–28. https://doi.org/
10.7554/eLife.54302.
Vela, J.M., Dalmau, I., Gonz´
alez, B., Castellano, B., 1995. Morphology and distribution of
microglial cells in the young and adult mouse cerebellum. J. Comp. Neurol. 361,
602–616. https://doi.org/10.1002/cne.903610405.
Wang, S.S., Denk, W., H¨
ausser, M., 2000. Coincidence detection in single dendritic spines
mediated by calcium release. Nat. Neurosci. 3, 1266–1273. https://doi.org/
10.1038/81792.
Wang, Z., Xu, N.L., Wu, C.P., Duan, S., Poo, M.M., 2003. Bidirectional changes in spatial
dendritic integration accompanying long-term synaptic modifications. Neuron 37,
463–472. https://doi.org/10.1016/S0896-6273(02)01189-3.
16
Y. Yamawaki et al.
Current Research in Neurobiology 3 (2022) 100028
Xanthos, D.N., Sandkühler, J., 2014. Neurogenic neuroinflammation: inflammatory CNS
reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53. https://
doi.org/10.1038/nrn3617.
Yamamoto, M., Kim, M., Imai, H., Itakura, Y., Ohtsuki, G., 2019. Microglia-triggered
plasticity of intrinsic excitability modulates psychomotor behaviors in acute
cerebellar inflammation. Cell Rep. 28, 2923–2938. https://doi.org/10.1016/j.
celrep.2019.07.078 e8.
Yamauchi, T., Makinodan, M., Toritsuka, M., Okumura, K., Kayashima, Y., Ishida, R.,
Kishimoto, N., Takahashi, M., Komori, T., Yamaguchi, Y., Takada, R., Yamamuro, K.,
Kimoto, S., Yasuda, Y., Hashimoto, R., Kishimoto, T., 2021. Tumor necrosis factor-α
expression aberration of M1/M2 macrophages in adult high-functioning autism
spectrum disorder. Autism Res. 14, 2330–2341. https://doi.org/10.1002/aur.2585.
Yu, Y.C., Bultje, R.S., Wang, X., Shi, S.H., 2009. Specific synapses develop preferentially
among sister excitatory neurons in the neocortex. Nature 458, 501–504. https://doi.
org/10.1038/nature07722.
Zhan, Y., Paolicelli, R.C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F.,
Vyssotski, A.L., Bifone, A., Gozzi, A., Ragozzino, D., Gross, C.T., 2014. Deficient
neuron-microglia signaling results in impaired functional brain connectivity and
social behavior. Nat. Neurosci ...