| First Author | Sigalas C | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 32 | Pages | 11196-208 |
| PubMed ID | 26269630 | Mgi Jnum | J:226024 |
| Mgi Id | MGI:5695679 | Doi | 10.1523/JNEUROSCI.5222-14.2015 |
| Citation | Sigalas C, et al. (2015) High-Affinity Nicotinic Receptors Modulate Spontaneous Cortical Up States In Vitro. J Neurosci 35(32):11196-208 |
| abstractText | Nicotinic acetylcholine receptors (nAChRs) play an important role in the modulation of many cognitive functions but their role in integrated network activity remains unclear. This is at least partly because of the complexity of the cholinergic circuitry and the difficulty in comparing results from in vivo studies obtained under diverse experimental conditions and types of anesthetics. Hence the role of nAChRs in the synchronization of cortical activity during slow-wave sleep is still controversial, with some studies showing they are involved in ACh-dependent EEG desynchronization, and others suggesting that this effect is mediated exclusively by muscarinic receptors. Here we use an in vitro model of endogenous network activity, in the form of recurring self-maintained depolarized states (Up states), which allows us to examine the role of high-affinity nAChRs on network dynamics in a simpler form of the cortical microcircuit. We find that mice lacking nAChRs containing the beta2-subunit (beta2-nAChRs) have longer and more frequent Up states, and that this difference is eliminated when beta2-nAChRs in wild-type mice are blocked. We further show that endogenously released ACh can modulate Up/Down states through the activation of both beta2- and alpha7-containing nAChRs, but through distinct mechanisms: alpha7-nAChRs affect only the termination of spontaneous Up states, while beta2-nAChRs also regulate their generation. Finally we provide evidence that the effects of beta2-subunit-containing, but not alpha7-subunit-containing nAChRs, are mediated through GABAB receptors. To our knowledge this is the first study documenting direct nicotinic modulation of Up/Down state activity. SIGNIFICANCE STATEMENT: Through our experiments we were able to uncover a clear and previously disputed effect of nicotinic signaling in synchronized activity of neuronal networks of the cortex. We show that both high-affinity receptors (containing the beta2-subunit, beta2-nAChRs) and low-affinity receptors (containing the alpha7-subunit, alpha7-nAChRs) can regulate cortical network function exhibited in the form of Up/Down states. We further show that the effects of beta2-nAChRs, but not alpha7-nAChRs, are mediated through the activation of GABAB receptors. These results suggest a possible synthesis of seemingly contradictory results in the literature and could be valuable for informing computational models of cortical function and for guiding the search for therapeutic interventions. |
