Loss of α7 Nicotinic Acetylcholine Receptors in GABAergic Neurons Causes Sex-dependent Decreases in Radial Glia-like Cell Quantity and Impairments in Cognitive and Social Behavior

Overview

Journal Brain Struct Funct

Specialty Neurology

Date 2021 Jan 5

PMID 33398432

Citations 6

Authors

Samir A Nacer

Ayland C Letsinger

Simone Otto

Jemma Strauss DeFilipp

Viktoriya D Nikolova

Natallia V Riddick

Korey D Stevanovic

Jesse D Cushman

Jerrel L Yakel

Affiliations

Soon will be listed here.

Abstract

The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the α7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out α7 nAChRs in GABAergic neurons. Deletion of α7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

Citing Articles

Circadian Alterations in Brain Metabolism Linked to Cognitive Deficits During Hepatic Ischemia-Reperfusion Injury Using [H-C]-NMR Metabolomics.

Li Y, Liu Y, He Z, Li Z, Xiang H Biomedicines. 2024; 12(11).

PMID: 39595102 PMC: 11592224. DOI: 10.3390/biomedicines12112536.

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies.

Arunrungvichian K, Vajragupta O, Hayakawa Y, Pongrakhananon V ACS Pharmacol Transl Sci. 2024; 7(1):28-41.

PMID: 38230275 PMC: 10789132. DOI: 10.1021/acsptsci.3c00138.

Genetic deletion of α7 nAChRs reduces hippocampal granule and pyramidal cell number in both sexes but impairs pattern separation in males only.

Letsinger A, Nacer S, Stevanovic K, Larson G, DeFilipp J, Cushman J Front Neurosci. 2023; 17:1244118.

PMID: 37746145 PMC: 10513752. DOI: 10.3389/fnins.2023.1244118.

Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions.

Goral R, Harper K, Bernstein B, Fry S, Lamb P, Moy S Front Behav Neurosci. 2022; 16:1067409.

PMID: 36505727 PMC: 9730538. DOI: 10.3389/fnbeh.2022.1067409.

In the pursuit of new social neurons. Neurogenesis and social behavior in mice: A systematic review.

Garcia-Gomez L, Castillo-Fernandez I, Perez-Villalba A Front Cell Dev Biol. 2022; 10:1011657.

PMID: 36407114 PMC: 9672322. DOI: 10.3389/fcell.2022.1011657.

References

Piterkin P, Cole E, Cossette M, Gaskin S, Mumby D . A limited role for the hippocampus in the modulation of novel-object preference by contextual cues. Learn Mem. 2008; 15(10):785-91. DOI: 10.1101/lm.1035508. View

Kalman E, Keay K . Hippocampal volume, social interactions, and the expression of the normal repertoire of resident-intruder behavior. Brain Behav. 2017; 7(9):e00775. PMC: 5607542. DOI: 10.1002/brb3.775. View

Hernandez C, Cortez I, Gu Z, Colon-Saez J, Lamb P, Wakamiya M . Research tool: Validation of floxed α7 nicotinic acetylcholine receptor conditional knockout mice using in vitro and in vivo approaches. J Physiol. 2014; 592(15):3201-14. PMC: 4146370. DOI: 10.1113/jphysiol.2014.272054. View

Wei J, Davis K, Wu H, Wu J . Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications. Biochemistry. 2004; 43(20):6182-9. DOI: 10.1021/bi0496992. View

Jonasson Z . Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci Biobehav Rev. 2005; 28(8):811-25. DOI: 10.1016/j.neubiorev.2004.10.006. View

Amrein I, Slomianka L, Poletaeva I, Bologova N, Lipp H . Marked species and age-dependent differences in cell proliferation and neurogenesis in the hippocampus of wild-living rodents. Hippocampus. 2004; 14(8):1000-10. DOI: 10.1002/hipo.20018. View

Gao J, Wang H, Liu Y, Li Y, Chen C, Liu L . Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress. Med Sci Monit. 2014; 20:499-512. PMC: 3976216. DOI: 10.12659/MSM.890589. View

Gu Z, Yakel J . Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron. 2011; 71(1):155-65. PMC: 3134790. DOI: 10.1016/j.neuron.2011.04.026. View

Chowdhury N, Quinn J, Fanselow M . Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice. Behav Neurosci. 2005; 119(5):1396-402. DOI: 10.1037/0735-7044.119.5.1396. View

10.

Vicidomini C, Guo N, Sahay A . Communication, Cross Talk, and Signal Integration in the Adult Hippocampal Neurogenic Niche. Neuron. 2020; 105(2):220-235. PMC: 7184932. DOI: 10.1016/j.neuron.2019.11.029. View

11.

Galea L . Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents. Brain Res Rev. 2007; 57(2):332-41. DOI: 10.1016/j.brainresrev.2007.05.008. View

12.

Bates R, Stith B, Stevens K, Adams C . Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. Neuroscience. 2014; 273:52-64. PMC: 4122271. DOI: 10.1016/j.neuroscience.2014.05.004. View

13.

Ludewig K, Geyer M, Vollenweider F . Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia. Biol Psychiatry. 2003; 54(2):121-8. DOI: 10.1016/s0006-3223(02)01925-x. View

14.

Brydges N, Moon A, Rule L, Watkin H, Thomas K, Hall J . Sex specific effects of pre-pubertal stress on hippocampal neurogenesis and behaviour. Transl Psychiatry. 2018; 8(1):271. PMC: 6288078. DOI: 10.1038/s41398-018-0322-4. View

15.

Segklia K, Stamatakis A, Stylianopoulou F, Lavdas A, Matsas R . Increased Anxiety-Related Behavior, Impaired Cognitive Function and Cellular Alterations in the Brain of Cend1-deficient Mice. Front Cell Neurosci. 2019; 12:497. PMC: 6361865. DOI: 10.3389/fncel.2018.00497. View

16.

Rowley T, Payappilly J, Lu J, Flood P . The antinociceptive response to nicotinic agonists in a mouse model of postoperative pain. Anesth Analg. 2008; 107(3):1052-7. DOI: 10.1213/ane.0b013e318165e0c0. View

17.

Asrican B, Paez-Gonzalez P, Erb J, Kuo C . Cholinergic Circuit Control of Postnatal Neurogenesis. Neurogenesis (Austin). 2016; 3(1). PMC: 4959609. DOI: 10.1080/23262133.2015.1127310. View

18.

Westenbroek C, den Boer J, Veenhuis M, Ter Horst G . Chronic stress and social housing differentially affect neurogenesis in male and female rats. Brain Res Bull. 2004; 64(4):303-8. DOI: 10.1016/j.brainresbull.2004.08.006. View

19.

Linn M, Petersen A . Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Dev. 1985; 56(6):1479-98. View

20.

Gu Z, Smith K, Alexander G, Guerreiro I, Dudek S, Gutkin B . Hippocampal Interneuronal α7 nAChRs Modulate Theta Oscillations in Freely Moving Mice. Cell Rep. 2020; 31(10):107740. PMC: 7333865. DOI: 10.1016/j.celrep.2020.107740. View