Impaired Hippocampal Theta Oscillations in the Mice Null Alpha7 Nicotinic Acetylcholine Receptors

Abstract

Nicotinic acetylcholine receptor (nAChR) a7 subunits are among the most ancient of vertebrate nAChR subunits and have the capacity to assemble as homomers. Naturally expressed a7-nAChRs in the central nervous system play a critical role in modulating the release of various neurotransmitters, neurite outgrowth, and even neuronal survival or death [1]. a7-nAChRs also have been implicated in development, differentiation, and disease of the nervous system, as well as being targets of nicotine action. a7-nAChRs are highly expressed in the hippocampus, a brain structure associated to learning, memory, and cognitive functions. Accumulating lines of evidence demonstrate that a7-nAChRs are key targets in mediating cholinergic modulations of cognition [2]. Hippocampus plays an important role in declarative memory and learning, and possesses a large amplitude rhythm at theta frequency (4–12 Hz), which is postulated to support mnemonic processes in humans and rodents [3,4]. It has been reported that nicotine modulates hippocampal theta oscillations likely through a4b2-nAChRs [5,6], but the role of a7-nAChRs in hippocampal theta oscillations is still uncertain. Whether or not a7-nAChR knockout (KO) mice exhibit hippocampal theta oscillation is unknown. Here, we present, for the first time, that a7-nAChR KO mice selectively lack hippocampal theta oscillations. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the Barrow Neurological Institute. The data were collected from 27 hippocampal slices from 8 wild-type (WT) mice (postnatal 28 3 days) and 16 hippocampal slices from 6 a7-nAChR KOmice (postnatal 26 3 days, P > 0.05 between WT and a7-nAChR KO mice, t-test). Transverse hippocampal slices (450 lm) were prepared as previously reported [7]. External solution contained (mM) NaCl 124, NaHCO3 26, KCl 3, KH2PO4 1.2, CaCl2 2.4, MgSO4 1.3, D-glucose 10, which was continuously bubbled with 95% O2–5% CO2 during the entire experimental period. Field potential recordings were performed in the CA1 cell layer using a glass electrode filled with 2 M NaCl. During recordings, the recording chamber was set to 31°C. Hippocampal theta oscillations were induced by bath application of 50 lM carbachol (CCh) for 50–60 min, as previously described [5,8]. Under this experimental protocol, only one slice showed no response to CCh in 27 tested slices from WT mice, while six slices showed no response to CCh in 16 tested slices from a7-nAChR KO mice. As shown in Figure 1, in the continuous presence of 50 lM CCh, there were typically three types of oscillations, slow (delta: 0.5 0.06 Hz, n = 18), theta (6.3 0.46 Hz, n = 23), and super-fast (146.1 7.0 Hz, n = 19) oscillations in WT hippocampal slices (Figure 1A). However, in a7-nAChR KO hippocampal