Abstract
Negative allosteric modulators, such as lynx1 and lynx2, directly interact with nicotinic acetylcholine receptors (nAChRs). The nAChRs are integral to cholinergic signaling in the brain and have been shown to mediate different aspects of cognitive function. Given the interaction between lynx proteins and these receptors, we examined whether these endogenous negative allosteric modulators are involved in cognitive behaviors associated with cholinergic function. We found both cell-specific and overlapping expression patterns of lynx1 and lynx2 mRNA in brain regions associated with cognition, learning, memory, and sensorimotor processing, including the prefrontal cortex (PFC), cingulate cortex, septum, hippocampus, amygdala, striatum, and pontine nuclei. Since lynx proteins are thought to play a role in conditioned associations and given the expression patterns across brain regions, we first assessed whether lynx knockout mice would differ in a cognitive flexibility task. We found no deficits in reversal learning in either the lynx1–/– or lynx2–/– knockout mice. Thereafter, sensorimotor gating was examined with the prepulse inhibition (PPI) assessment. Interestingly, we found that both male and female lynx1–/– mice exhibited a deficit in the PPI behavioral response. Given the comparable expression of lynx2 in regions involved in sensorimotor gating, we then examined whether removal of the lynx2 protein would lead to similar behavioral effects. Unexpectedly, we found that while male lynx2–/– mice exhibited a decrease in the baseline startle response, no differences were found in sensorimotor gating for either male or female lynx2–/– mice. Taken together, these studies provide insight into the expression patterns of lynx1 and lynx2 across multiple brain regions and illustrate the modulatory effects of the lynx1 protein in sensorimotor gating.
Highlights
Given that the prefrontal cortex (PFC), cingulate cortex, and septum have been implicated in cognitive function, we examined lynx1 and lynx2 mRNA expression across these brain regions
Of further interest, when examined at lower magnification (Figure 2b), the localization of lynx2 in the dorsal striatum resembled striosome expression patterns (Brimblecombe and Cragg, 2017), this localization will need to be confirmed in further studies
Given that males and females fluctuate in their hormonal levels across varying daily cycles, a future study controlling for the relative levels of testosterone and estrogen will be essential to more clearly define such an interaction. These studies demonstrate a role for lynx1 in various aspects of cognitive processing with sex-specific effects. It will be important in future studies to ascertain the cell-type specific patterns of expression for the lynx proteins within different brain circuits and to precisely assess the potential competition of positive and negative allosteric modulators of the nicotinic acetylcholine receptors (nAChRs) at the synaptic level between sexes
Summary
The cholinergic system controls a variety of complex cognitive processes, such as attention, sensorimotor gating, cognitive flexibility, reinforcement, learning, and memory (Court et al, 1999; Miwa et al, 2006, 2011; Tekinay et al, 2009; Zhang et al, 2010; de la Salle et al, 2013; Freitas et al, 2013; Chen et al, 2018, 2020; Solari and Hangya, 2018; Anderson et al, 2020; Sherafat et al, 2021).Lynx and Lynx Functional CharacterizationIntegral to the cholinergic system are the nicotinic acetylcholine receptors (nAChRs). The nAChRs exhibit various allosteric binding sites, which allow for modulation of the pharmacokinetics associated with receptor activation and desensitization (Le Novere et al, 2002). The lynx and lynx proteins are classified as negative allosteric modulators of the cholinergic system through their actions in reducing the activity of the nAChRs in the presence of an agonist (Ibanez-Tallon et al, 2002; Kobayashi et al, 2014; Nichols et al, 2014; George et al, 2017). Lynx proteins dampen the cholinergic system’s activity, which has been proposed to subsequently underlie changes in memory, learning, and plasticity (Miwa et al, 2006; Morishita et al, 2010)
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