AKT2 modulates astrocytic nicotine responses in vivo.

Lombardi, A. M.; Wong, H.; Bower, M. E.; Milstead, R.; Borski, C.; Schmitt, E.; Griffioen, M.; LaPlante, L. E.; Ehringer, M. A.; Stitzel, J. A.; Hoeffer, C. A. A.

doi:10.1101/2024.05.31.596856

bioRxiv · 10.1101/2024.05.31.596856

AKT2 modulates astrocytic nicotine responses in vivo.

Lombardi, A. M.·Wong, H.·Bower, M. E.·Milstead, R.·Borski, C.·Schmitt, E.·Griffioen, M.·LaPlante, L. E.·Ehringer, M. A.·Stitzel, J. A.·Hoeffer, C. A. A.

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Abstract

A greater understanding of the neurobiology of nicotine is needed to reduce or prevent chronic addiction, ameliorate detrimental nicotine withdrawal effects, and improve cessation rates. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), 4{beta}2 and 7. Protein kinase B-{beta} (Pkb-{beta} or Akt2) expression is restricted to astrocytes in mice and humans and is activated by nicotine. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice. For in/ex vivo studies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 g/mL) or following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed enhanced acute responses and reduced area following chronic exposure. In culture, we found 100 M nicotine sufficient for morphological changes and blocking 7 or 4{beta}2 nAChRs prevented observed morphologic changes. We performed conditioned place preference (CPP) in Akt2 cKO mice, which revealed reduced nicotine preference in cKO mice compared to controls. Finally, we performed RNASeq comparing nicotine- and LPS-mediated gene expression, identifying robust differences between these two astrocytic stimuli. These findings show the importance of nAChRs and AKT2 signaling in the astrocytic response to nicotine. Main PointsO_LINicotine regulates astrocytes in vivo: acute exposure boosts complexity; chronic exposure diminishes it. C_LIO_LIAKT2, expressed in astroglia, modulates morphological changes in response to nicotine and nicotine-dependent conditioned place preference. C_LI

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Lombardi, A. M., Wong, H., Bower, M. E., Milstead, R., Borski, C., Schmitt, E., Griffioen, M., LaPlante, L. E., Ehringer, M. A., Stitzel, J. A., Hoeffer, C. A. A.. 2024-06-01. AKT2 modulates astrocytic nicotine responses in vivo.. https://doi.org/10.1101/2024.05.31.596856

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