Negative Modulation of α4β2* Nicotinic Acetylcholine Receptors During Postnatal Maturation of the Mouse Prefrontal Cortex

Abstract

Acetylcholine (ACh) signalling within the medial prefrontal cortex (mPFC) is important for the normal development and function of prefrontal cognitive networks. Layer VI of the mPFC is highly populated with pyramidal neurons that express the α4β2* subtype of nicotinic acetylcholine receptor (nAChR), and the activation of these receptors by ACh is central to its function in this region. These receptors can be negatively modulated through several forms of inhibition. For example, nicotine potently desensitizes nAChRs to ACh activation, while the endogenous progesterone‐derived neurosteroid 3α‐hydroxy‐5α‐prenan‐20‐one (allopregnanolone; ALLO) inhibits nAChR activation by ACh through a presumed negative allosteric modulation. Both forms of inhibition mediated by nicotine and ALLO have been demonstrated for α4β2* nAChRs located on mPFC layer VI neurons in young postnatal mice. However, the relative strength for both forms of inhibition in mature mice, compared with the young postnatal age, is not clear. In addition, the mechanism of action for ALLO inhibition of α4β2* nAChRs is not well understood. Using whole‐cell electrophysiology, we measured the ability of both nicotine (300 nM) and ALLO (10 μM) to inhibit 1 mM ACh activation of α4β2* nAChRs located on mPFC layer VI neurons from male and female CD1‐strain mice at postnatal day (P)15‐20 (young postnatal age) and P80‐120 (adulthood). For nicotine, nAChR desensitization was greater at P15‐20 than at P80‐120, and this result was driven by an effect of postnatal age in male mice only. Conversely, ALLO inhibited nAChR function to a similar degree at both P15‐20 and P80‐120. Ongoing ACh binding experiments aim to determine the mechanism of action for ALLO inhibition of these receptors at both ages. Results from this study confirm that the endogenous neurosteroid ALLO inhibits mPFC α4β2* nAChRs in adulthood as it does in young postnatal life. Developmental changes to the magnitude of nicotine desensitization but not ALLO inhibition suggests that different factors regulate each type of negative modulation at α4β2* nAChRs, and that these factors are differentially altered during postnatal maturation of the mPFC. Support or Funding Information Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant 2019‐04989 to CDCB