Functional Changes to the Modulation of α4β2* Nicotinic Acetylcholine Receptors during Postnatal Maturation

Abstract

The neurotransmitter acetylcholine (ACh) acting at its α4β2* subtype of nicotinic acetylcholine receptor (nAChR) within the cerebral cortex plays an important role to support cognitive functions. ACh normally initiates a robust excitatory response at α4β2* nAChRs, although this activity may be modulated by a number of mechanisms that alter receptor function. Negative receptor modulation may occur via desensitization by the competitive agonist nicotine or via presumed negative allosteric modulation by the endogenous progesterone-derived neurosteroid 3α-hydroxy-5α-prenan-20-one (allopregnanolone; ALLO). Conversely, positive modulation may occur via positive allosteric modulation by the alkaloid galantamine. Although each form of modulation has been demonstrated to occur in α4β2* nAChRs located on pyramidal neurons within layer VI of the medial prefrontal cortex (mPFC) in young postnatal male mice, the presence and relative strength of modulation in young postnatal female mice, and at maturity for both sexes, is unclear. Using whole-cell electrophysiology in mFPC layer VI neurons, we measured the ability of nicotine (300 nM), ALLO (10 μM), and galantamine (0.1 μM) to modulate ACh activation of α4β2* nAChRs in male and female mice at postnatal day (P)15-20 (young postnatal age) and P80-120 (adulthood). For nicotine, nAChR desensitization at P15-20 was greater than at P80-120 and this result was driven by an effect of postnatal age in male mice only. In contrast, ALLO inhibited nAChR function to a similar degree at both P15-20 and P80-120. Galantamine potentiated nAChR function to a similar degree at both P15 and P80-120, although this potentiation was significantly greater in females than in males at each age. Results from this study suggest that distinct factors are involved in each type of receptor modulation, which are differentially altered during postnatal maturation and across biological sex. Future studies will focus on mechanisms by which these factors influence the modulation of α4β2* nAChRs during postnatal maturation.