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bioRxiv · 10.1101/2025.06.18.660362

Nicotinic Modulation of Fast-spiking Neurons in Rat Somatosensory Cortex Across Development

Haga, C. W.·Koenig, J. A.·Cramer, N. P.·Chandra, R.·Keller, A.
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Abstract

Signaling at nicotinic acetylcholine receptors (nAChRs) is vital for normal development of cerebral cortical circuits. These developing circuits are also shaped by fast-spiking (FS) inhibitory cortical neurons. While nicotinic dysfunction in FS neurons is implicated in a number of psychiatric and neurodevelopmental disorders, FS neurons are thought to not have nicotinic responses in adults. Here, we establish a timeline of FS neuron response to nicotine pre- and postsynaptically in primary somatosensory cortex in male and female rats. We found that nicotine increases the frequency of spontaneous synaptic inputs to FS neurons during the second postnatal week, and this effect persisted through development. In contrast, FS neurons in S1 had no postsynaptic responses to nicotine from as early as they can be reliably identified. This was not attributable to receptor desensitization, and we further revealed that FS neurons express abundant mRNA for several nAChR subunits, beginning early in development. To determine why FS neurons do not respond to nicotine, despite expressing these receptors, we probed for the expression of lynx1, a negative nicotinic modulator. Lynx1 mRNA was expressed in FS neurons from early development, with expression increasing dramatically during the second postnatal week. SIGNIFICANCE STATEMENTSignaling at nicotinic receptors is critical for development of cortical circuits. These circuits are also shaped by fast-spiking (FS) inhibitory neurons. We reveal how these developmental processes interact, by establishing a timeline of nicotinic effects on FS neurons in rats. We find that nicotine presynaptically regulates inputs to FS neurons from early development. However, FS neurons at all ages lack postsynaptic responses to nicotine, despite expressing nicotinic receptor mRNA. This might be due to the expression of lynx1, a negative nicotinic receptor modulator, which we identify in FS neurons as early as the first postnatal week. This work reveals novel aspects of development, relevant to both normal cortical development and the neuropsychiatric pathologies associated with abnormal FS neurons and nicotinic development.

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Haga, C. W., Koenig, J. A., Cramer, N. P., Chandra, R., Keller, A.. 2025-06-22. Nicotinic Modulation of Fast-spiking Neurons in Rat Somatosensory Cortex Across Development. https://doi.org/10.1101/2025.06.18.660362

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