Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

Abstract

Dendritic spine turnover becomes limited in the adult cerebral cortex. Identification of specific aspects of spine dynamics that can be unmasked in adulthood and its regulatory molecular mechanisms could provide novel therapeutic targets for inducing plasticity at both the functional and structural levels for robust recovery from brain disorders and injuries in adults. Lynx1, an endogenous inhibitor of nicotinic acetylcholine receptors, was previously shown to increase its expression in adulthood and thus to limit functional ocular dominance plasticity in adult primary visual cortex (V1). However, the role of this "brake" on spine dynamics is not known. We examined the contribution of Lynx1 on dendritic spine turnover before and after monocular deprivation (MD) in adult V1 with chronic in vivo imaging using two-photon microscopy and determined the spine turnover rate of apical dendrites of layer 5 (L5) and L2/3 pyramidal neurons in adult V1 of Lynx1 knock-out (KO) mice. We found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1. After MD, adult Lynx1-KO mice selectively exhibit higher rate of spine loss with no difference in gain rate in L5 neurons compared with control wild-type counterparts, revealing a key signature of spine dynamics associated with robust functional plasticity in adult V1. Overall, Lynx1 could be a promising therapeutic target to induce not only functional, but also structural plasticity at the level of spine dynamics in the adult brain.

Nicotinic regulation of experience-dependent plasticity in visual cortex

“…Sajo et al also demonstrated that after MD, while spine gain rate of layer 5 neurons becomes comparable between adult Lynx1KO mice and adult WT mice due to MD-induced increase in spine gain in WT mice (Hofer et al, 2009), spine loss rate remains significantly higher in Lynx1KO mice compared to WT matched controls in both layer 5 and 2/3 neurons (Sajo et al, 2016). These results suggested that, while spine gain rate correlates well with the residual plasticity in the normal adult V1, higher spine loss seems to be a good correlate of elevated juvenile-like functional plasticity in adult Lynx1KO mice.…”

“…If nicotinic cholinergic signaling could regulate critical period plasticity, then how would then plasticity become severely restricted in adulthood even in the remaining presence of robust basal forebrain cholinergic innervation? Here we introduce Lynx1, an allosteric cholinergic modulator that increases into adulthood after critical period, and review its contribution to regulate functional and structural plasticity in the V1 (Bukhari et al, 2015; Morishita et al, 2010; Sajo et al, 2016). The discovery of the role of nicotinic cholinergic modulator Lynx1 as a plasticity regulator has given light to a new perspective – the brain is intrinsically plastic even in adulthood, but is actively masked by molecular plasticity “brakes” (Bavelier et al, 2010).…”

“…Through the use of in vivo chronic imaging using two-photon microscopy, Sajo et al recently examined the contribution of Lynx1 on dendritic spine turnover before and after MD in the adult V1 by measuring the spine turnover rate of apical dendrites of layer 5 and 2/3 pyramidal neurons in adult Lynx1 KO mice (Sajo et al, 2016). They found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1.…”

“…These results suggested that, while spine gain rate correlates well with the residual plasticity in the normal adult V1, higher spine loss seems to be a good correlate of elevated juvenile-like functional plasticity in adult Lynx1KO mice. Interestingly, in adult Lynx1KO neurons, MD induced a reduction in spine loss rate, with no change in gain rate (Sajo et al, 2016), in contrast to adult wild type L5 neurons, where it is known that MD increases their spine gain rate with no change in loss rate (Hofer et al, 2009). Given that juvenile mouse barrel cortex also similarly exhibits whisker-trimming-induced reduction of spine loss (Zuo et al, 2005), the experience-dependent changes observed in Lynx1KO mice reflect characteristics of the juvenile but not adult WT brain.…”

Transplantation of GABAergic interneurons for cell-based therapy

“…The inability for CGE-derived neurons to induce plasticity also suggests that the mechanisms required to home the transplanted cells into the host cortical network are not enough to elicit functional reorganization. Endogenous critical period closure has been associated with the expression of molecular brakes that stabilize mature cortical networks (Bavelier et al, 2010; Morishita et al, 2010; Sajo et al, 2016). Transplanted PV and SST cells may alter the expression of such brakes and thus allow host cells to rewire upon sensory deprivation.…”