Rat Anti-Chicken Neuronal Receptor for Acetylcholine Heterohybridoma [mAb 381]

Disruption in cholinergic signaling has been linked to many environmental and/or pathological conditions known to modify adult neurogenesis. The 7 nAChRs are in the family of cys-loop receptor channels which have been shown to be neuroprotective in adult neurons and are thought to be critical for survival and integration of immature neurons. However, in developing neurons, poor calcium buffering may cause 7 nAChR activation to be neurotoxic. To investigate whether the 7 nAChR regulates neurogenesis in the hippocampus, we used a combination of mouse genetics and imaging to quantify neural stem cell (NSC) densities located in the dentate gyrus of adult mice. In addition, we considered whether the loss of 7 nAChRs had functional consequences on a spatial discrimination task that is thought to rely on pattern separation mechanisms. We found that the loss of 7 nAChRs resulted in increased neurogenesis in male mice only, while female mice showed increased cell divisions and intermediate progenitors but no change in neurogenesis. Knocking out the 7 nAChR from nestin(+) NSCs and their progeny showed signaling in these cells contributes to regulating neurogenesis. In addition, male, but not female, mice lacking 7 nAChRs performed significantly worse in the spatial discrimination task. This task was sexually dimorphic in wild-type mice, but not in the absence of 7 nAChRs. We conclude that 7 nAChRs regulate adult neurogenesis and impact spatial discrimination function in male, but not female mice, via a mechanism involving nestin(+) NSCs and their progeny.

Alpha7 nicotinic acetylcholine receptors (nAChRs) are promising novel targets for the treatment of neurocognitive disorders. Although the cognitive enhancer potential of alpha7 nAChR agonists and positive allosteric modulators (PAMs) has been confirmed in several preclinical animal models, there are only sparse in vivo electrophysiological data on their effects on the firing activity and excitability of neurons. The present study investigated and compared local effects of alpha7 nAChR agonist PHA-543613 and PAMs PNU-120596 and NS-1738 on the spontaneous and N-methyl-D-aspartate-evoked (NMDA-evoked) firing rate of rat CA1 hippocampal pyramidal cells, in vivo. Furthermore, effects of alpha7 nAChR antagonist methyllycaconitine (MLA) and GABA were also tested. Results showed substantially different effects of the alpha7 nAChR agonist and PAMs. While PNU-120596 and NS-1738 predominantly and significantly increased both spontaneous and NMDA-evoked firing rate of the neurons, application of PHA-543613 resulted in almost equal distribution of facilitatory and inhibitory effects. The increase of the NMDA-evoked firing rate exerted by NS-1738 was superadditive over the sum of the single effects of NMDA and NS-1738. The simultaneous application of alpha7 nAChR agonist PHA-543613 and PAM NS-1738 resulted in additive increase of both spontaneous and NMDA-evoked firing rate. However, NS-1738 counteracted inhibitory effects of PHA-543613 in 5 out of 6 neurons, resulting in a synergistic potentiation of their firing responses to NMDA. Our results suggest that alpha7 nAChR PAMs increase neuronal excitability more potently than agonists, while the remarkable occurrence of inhibitory effects of PHA-543613 (possibly originating from receptor desensitization) implies that agonists may exert neuroprotective effects.