Endogenous Signaling through  7-Containing Nicotinic Receptors Promotes Maturation and Integration of Adult-Born Neurons in the Hippocampus

Abstract

Neurogenesis in the dentate gyrus occurs throughout adult mammalian life and is essential for proper hippocampal function. Early in their development, adult-born neurons express homomeric ␣7-containing nicotinic acetylcholine receptors (␣7-nAChRs) and receive direct cholinergic innervation. We show here that functional ␣7-nAChRs are necessary for normal survival, maturation, and integration of adult-born neurons in the dentate gyrus. Stereotaxic retroviral injection into the dentate gyrus of wild-type and ␣7-knock-out (␣7KO) male and female mice was used to label and birthdate adult-born neurons for morphological and electrophysiological measures; BrdU (5-bromo-2-deoxyuridine) injections were used to quantify cell survival. In ␣7KO mice, we find that adult-born neurons develop with truncated, less complex dendritic arbors and display GABAergic postsynaptic currents with immature kinetics. The neurons also have a prolonged period of GABAergic depolarization characteristic of an immature state. In this condition, they receive fewer spontaneous synaptic currents and are more prone to die during the critical period when adult-born neurons are normally integrated into behaviorally relevant networks. Even those adult-born neurons that survive the critical period retain long-term dendritic abnormalities in ␣7KO mice. Interestingly, local infection with retroviral constructs to knockdown ␣7-mRNA mimics the ␣7KO phenotype, demonstrating that the relevant ␣7-nAChR signaling is cell autonomous. The results indicate a profound role for ␣7-nAChRs in adult neurogenesis and predict that ␣7-nAChR loss will cause progressive impairment in hippocampal circuitry and function over time as fewer neurons are added to the dentate gyrus and those that are added integrate less well.

Identification and Characterization of a G Protein-binding Cluster in α7 Nicotinic Acetylcholine Receptors

“…A mutation of the GPBC within ␣7 nAChRs was found sufficient to eliminate association with G␣ q as well as G␤ subunits in both PC12 and N2a cells. In preliminary studies, we found that individual mutations at the GPBC did not significantly impact G protein binding, 3 confirming that all four residues contribute to a G protein binding core within the ␣7 nAChR. In light of the similarity of this site with the G protein binding residues (RFFP) within the GIRK1 channel, it is plausible that a minimal consensus sequence consisting of RXYR 3 J. R. King and N. Kabbani, unpublished data.…”

“…Pharmacological inhibition of IP 3 Rs by xestospongin C appears sufficient to attenuate the ␣7 calcium signal at the GC. Varied responses to xestospongin C exist throughout the cell and suggest a role for compartment specific mechanisms.…”

“…In the hippocampus and cortex homomeric ␣7 and heteromeric ␣4␤2 nAChRs have been shown to contribute to neurotransmitter release and dendritic plasticity (2). Upon ligand activation, ␣7 nAChRs conduct cations into the cell (1)(2)(3)(4). However, because the receptor channel desensitizes within milliseconds (5) it is possible that ligand binding can also set into motion longer lived downstream signaling events.…”

Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb

“…During this stage, granule neurons also experience a switch of their GABA A -receptor reversal potential, which ultimately converts the initially excitatory (depolarizing) action of GABA into an inhibitory one (26). Intriguingly, cholinergic innervations of newborn neurons arising from basal forebrain regions of the MS/NDB are likely to participate, via nicotinic receptor activation, in this developmental switch (33).…”

Bis(12)-Hupyridone, a Promising Multi-Functional Anti-Alzheimer’s Dimer Derived from Chinese Medicine

“…7). As 7nAChR is essential for neuronal differentiation in the rat brain, and loss of 7nAChR impairs the maturation of dendritic neurons in adult hippocampus (Campbell et al, 2010;Le Magueresse et al, 2006), our results provide a novel insight into the possible therapeutic potential of bis(12)-hupyridone in treating AD. To date, as other clinically used anti-AD drugs such as huperzine A, donepezil and tacrine have also shown some activities in inducing neurite outgrowth in different neuronal cell lines in vitro (Table 4), it would be quite interesting to compare their effects on promoting neuronal differentiation in certain types of neurons, for example, neural stem cells with bis(12)-hupyridone (Cui et al, 2011a;De Ferrari et al, 1998;Oda et al, 2007;Sortino et al, 2004;Tang et al, 2005).…”