Alterations of cortical pyramidal neurons in mice lacking high-affinity nicotinic receptors

Abstract

The neuronal nicotinic acetylcholine receptors (nAChRs) are allosteric membrane proteins involved in multiple cognitive processes, including attention, learning, and memory. The most abundant form of heterooligomeric nAChRs in the brain contains the β2-and α4-subunits and binds nicotinic agonists with high affinity. In the present study, we investigated in the mouse the consequences of the deletion of one of the nAChR components: the β2-subunit (β2 −/− ) on the microanatomy of cortical pyramidal cells. Using an intracellular injection method, complete basal dendritic arbors of 650 layer III pyramidal neurons were sampled from seven cortical fields, including primary sensory, motor, and associational areas, in both β2 −/− and WT animals. We observed that the pyramidal cell phenotype shows significant quantitative differences among different cortical areas in mutant and WT mice. In WT mice, the density of dendritic spines was rather similar in all cortical fields, except in the prelimbic/infralimbic cortex, where it was significantly higher. In the absence of the β2-subunit, the most significant reduction in the density of spines took place in this high-order associational field. Our data suggest that the β2-subunit is involved in the dendritic morphogenesis of pyramidal neurons and, in particular, in the circuits that contribute to the high-order functional connectivity of the cerebral cortex.cerebral cortex | dendrites | dendritic spines | long-range connections | global neuronal workspace N icotinic acetylcholine receptors (nAChRs) are members of the ligand-gated ion channel superfamily of neurotransmitter receptors. They are transmembrane pentamers made up of a single or multiple subunits from the 17 known nAChR subunit genes of the vertebrate genome (9α and 4β). In mammalian neurons, the combinatorial assembly of these subunits generates a broad diversity of receptors with various physiological and pharmacological properties (1). The most abundant form of nAChR heterooligomer in the brain contains the β2-and α4-subunits (2, 3). Moreover, pharmacological experiments and ligand-binding studies demonstrate that nAChRs containing the β2-subunit (β2*nAChRs) bind the neurotransmitter acetylcholine and the drug nicotine with high affinity (4).Strong evidence from diverse sources indicates that nAChRs are involved in cognitive functions in humans and in animal models, including attention and performance in working and associative memory (5). Moreover, alterations of levels of β2*nAChRs are frequently associated with disorders such as schizophrenia, Alzheimer's disease, and autism (6-8). The generation of transgenic mice lacking the β2-subunit (β2) provided a unique opportunity to study the effect of the chronic absence of this receptor on behavior and brain function (9). β2 −/− mice indeed show abnormal passive avoidance, impaired nicotine self-administration, and drug discrimination; they also exhibit a reduced nociceptive response to nicotine, decreased visual acuity, reduced locomotion in a familiar environment, a...

Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing

“…We showed that the balance of recurrent excitation and inhibition is disrupted in the case of awake β2 KO mice, and more specifically, the neuronal synchronicity is disrupted. It has been reported that the β2 subunit is involved in the dendritic morphogenesis of pyramidal neurons, and in particular, in the circuits that contribute to the high-order functional connectivity of the cerebral cortex (40). These defects in the maturation of the cerebral cortex that have been reported in the β2 KO mice could contribute to the observed behavioral deficits (4,13,16).…”

Nicotine induces dendritic spine remodeling in cultured hippocampal neurons

“…Although the present study focused on the semi-acute effect of nicotine within 2 h, more dramatic alterations such as spine density (Engert and Bonhoeffer 1999;Nagerl et al 2004) might be correlated to a more persistent type of plasticity. The relationship between the activity of nAChR and spine density has been recently shown; a region specific decrease in spine density is observed in b2 subunit deleted mice (Ballesteros-Yanez et al 2010;Lozada et al 2012). Notably, Lozada and colleagues have reported an acute (1 h) change in spine density in young mouse (P7) but not in older mouse (P15).…”

Synaptic Epigenesis and the Evolution of Higher Brain Functions

“…One way we are testing this vulnerability is by comparing the dendritic branching of pyramidal neurons in wild-type mice with animals lacking the b2-subunit of the nicotinic acetylcholine receptor (Ballesteros-Yáñez et al 2010). Loss of this subunit prevents the high-affinity binding of the neurotransmitter acetylcholine and, as a consequence, mice lacking the b2-subunit show a characteristic behavioral deficit: their exploratory drive, which is one of the most cognitive aspect of mouse behavior, is reduced, although their navigation abilities, a more automatic activity, are unaffected.…”