Differential Expression Patterns of Lynx Proteins and Involvement of Lynx1 in Prepulse Inhibition

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.

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

“…The effects of lynx proteins on nicotinic receptor function have so far been determined by heterologous expression systems, 36 knockout studies, 72 , 78 exogenous application of recombinant water-soluble lynx proteins, 79 , 80 and viral manipulation of expression in the brain. 39 , 81 We advance this field by revealing, in native tissue, complex endogenous regulation of optogenetic nicotinic responses by multiple GPI-anchored lynx proteins.…”

ADHD‐associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

“…LYNX1 encodes a cell membrane bound member of the Ly6/uPAR (LU) superfamily of proteins and interacts with nicotinic acetylcholine receptors. It is suggested to prevent excessive excitation by doing so (Sherafat et al, 2021). A microdeletion in a region containing the LYNX gene was shown previously in a family with neurodevelopmental disorders (ADHD, ASD, epilepsy, intellectual disability and developmental delay in three siblings) (J. Hu et al, 2015).…”

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

“…In expression systems, Ly6g6e potentiates α4β2 nicotinic responses and slows their desensitization ( 39 ), predicting cholinergic responses in Chrna5+ neurons would be resistant to desensitization, as has been implied by Chrna5 deletion work ( 16 ). On the other hand, Lynx2 is a negative nicotinic modulator that increases desensitization of α4β2 nicotinic receptors ( 61 ), and is selectively expressed in the medial PFC ( 81 ). While Lynx2 is thought to act intracellularly to reduce surface expression of α4β2 nicotinic receptors ( 39 ), it may act selectively on the (α4) 3 (β2) 2 receptor subtype which are lower affinity ( 65, 82 ) and indirectly promote expression of high affinity α5-containing (α4) 2 (β2) 2 α5 nicotinic receptors.…”

“…The effects of lynxes on nicotinic receptor function have so far been determined by heterologous expression systems ( 39, 61 ), knockout studies ( 61, 81 ), exogenous application of recombinant water-soluble lynx proteins ( 86, 87 ), and more recently viral overexpression in the brain ( 42, 88 ). Our results are highlight complex endogenous regulation of optogenetic nicotinic responses by multiple GPI-anchored lynxes.…”

“…The effects of lynx proteins on nicotinic receptor function have so far been determined by heterologous expression systems (Wu et al, 2015), knockout studies (Sherafat et al, 2021; Tekinay et al, 2009), exogenous application of recombinant water-soluble lynx proteins (Shenkarev et al, 2020; Thomsen et al, 2016), and viral manipulation of expression in the brain (Falk et al, 2021; Sadahiro et al, 2020). We advance this field by revealing, in native tissue, complex endogenous regulation of optogenetic nicotinic responses by multiple GPI-anchored lynx proteins.…”