Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1

Abstract

Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out (KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders.

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

“…In the visual cortex, neuroserpin expression is increased during the critical period and decreased following monocular deprivation (Wannier-Morino et al 2003). Removal of Lynx1, a negative regulator of adult plasticity, leads to experience-dependent elevation of tPA and increased plasticity, a process blocked by administration of neuroserpin (Bukhari et al 2015). In addition to this direct evidence linking neuroserpin to synaptic function, translational data from schizophrenic patients, a disorder characterized by improper synaptic function, showed dysregulation of neuroserpin (Hakak et al 2001;Vawter et al 2004;Brennand et al 2011;Wen et al 2014), and mice with dysregulated expression of neuroserpin show selective reduction of locomotor activity in novel environments, anxiety-like response on the O-maze, and neophobic response to novel objects (Madani et al 2003).…”

Nicotinic regulation of experience-dependent plasticity in visual cortex

“…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).…”

“…Assessment of OD plasticity in Lynx1 knockout (KO) mice found that removal of Lynx1 prolongs heightened V1 plasticity into adulthood but not without the possibility of “re-masking” the plasticity through active pharmacological blockade of nAChR signaling. In the follow up study, it was further examined to what extent elevated OD plasticity in adult Lynx1KO mice reflects juvenile forms of plasticity (Bukhari et al, 2015). In juvenile mice, the OD shift after 4 days of MD is mediated primarily by a decrease of deprived contralateral eye response in the V1(Sato and Stryker, 2008).…”

“…In juvenile mice, the OD shift after 4 days of MD is mediated primarily by a decrease of deprived contralateral eye response in the V1(Sato and Stryker, 2008). Bukhari et al demonstrated that when the normalized visual stimulus evoked firing rates of V1 neurons were compared between MD and no MD groups, the deprived contralateral eye response of adult Lynx1KO mice after MD is significantly decreased and the non-deprived ipsilateral eye response is just modestly increased, suggesting that removal of Lynx1 unmasks juvenile-like characteristic of experience-dependent plasticity (Bukhari et al, 2015). In addition, adult Lynx1 KO mice that underwent long-term MD during the V1 critical period to artificially induce visual functional impairment modeling amblyopia showed spontaneous recovery of visual acuity to normal levels simply when the visually deprived eye was reopened (Morishita et al, 2010).…”

“…Importantly, such juvenile form of structural plasticity becomes limited in the adult V1. Recent study showed that in the V1 of adult Lynx1 KO mice there is a significant MD-dependent density reduction of the stubby spines and thin spines (but not mushroom spine) of distal apical dendritic spines of the V1 neurons in layer II/III following MD in comparison to its WT counterparts (Bukhari et al, 2015). These results are consistent with previously published results demonstrating the correlation of stubby spine (Christoffel et al, 2011; Golden et al, 2013) and thin spine (Dumitriu et al, 2010) subtypes and brain plasticity.…”