Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Abstract

Experience-dependent cortical plasticity has been studied by using loss-of-function methods. Here, we take the complementary approach of using a genetic gain-of-function that enhances plasticity. We show that a constitutively active form of H-ras (H-ras G12V ), expressed presynaptically at excitatory synapses in mice, accelerates and enhances multiple, mechanistically distinct forms of plasticity in the developing visual cortex. In vivo, H-ras G12V not only increased the rate of ocular dominance change in response to monocular deprivation (MD), but also accelerated recovery from deprivation by reverse occlusion. In vitro, H-ras G12V expression decreased baseline presynaptic release probability and enhanced presynaptically expressed longterm potentiation (LTP). H-ras G12V expression also accelerated the increase following MD in the frequency of miniature excitatory potentials, mirroring accelerated plasticity in vivo. These findings demonstrate accelerated neocortical plasticity, which offers an avenue toward future therapies for many neurological and neuropsychiatric disorders.gain of function | monocular deprivation | mouse | ocular dominance | presynaptic long-term potentiation

CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory

“…Previous studies with HRas G12V mice suggest that an increase in ocular dominance plasticity, as well as in learning and memory, is accompanied by a lower synaptic release probability in the cortex (Kaneko et al, 2010; Kushner et al, 2005). Therefore, we investigated the release probability in the barrel cortex of WT, Ccr5 +/- and Ccr5 -/- mice, by measuring the attenuation rate of NMDA receptor mediated evoked EPSPs (Figure 7A) in the presence of the activity-dependent NMDA receptor antagonist MK-801 (Hessler et al, 1993).…”

“…Whole cell recordings were performed in L2/3 and field stimulation was applied to L4 in the same cortical column (Figure 6A), and LTP was induced using a 5 ms pre-post interval as described previously (Kaneko et al, 2010). In WT mice, L2/3 cells showed significant LTP in just 20% of cases while in Ccr5 +/- and Ccr5 -/- mice the same protocol produced LTP in 70% of cases (Figure 6B, χ 2 = 15.63, p<0.001, χ-squared test).…”

Modeling the Dynamic Interaction of Hebbian and Homeostatic Plasticity

“…These slots are created by PSD structural proteins (Huganir and Nicoll 2013, Kessels and Malinow 2009), some of which play roles in homeostatic plasticity (Shin et al 2012, Steinmetz and Turrigiano 2010, Sun and Turrigiano 2011). The synaptic strength, to the extent that it is determined by AMPARs, could be understood as the product of four elements: (1) the area of the PSD (which is increased by Hebbian LTP, which increases spine size: Harvey and Svoboda 2007, Kopec et al 2007, Matsuzaki et al 2004, Zhou et al 2004); (2) the density of AMPARs bound to slots in the PSD; (3) the efficacy of the AMPARs (4) the presynaptic efficacy, which also undergoes activity-dependent modification (Atwood and Karunanithi 2002, Kaneko et al 2010). If free AMPARs in the membrane and slots bind with first-order kinetics, then the PSD density of bound AMPARs can be further broken down as the product of (2a) membrane AMPAR density, known to be increased by TNF- α (Beattie et al 2002, Leonoudakis et al 2008, Stellwagen and Malenka 2006); (2b) PSD slot density; (2c) slot/AMPAR binding affinity.…”

Adult cortical plasticity following injury: Recapitulation of critical period mechanisms?

“…LTP) are thought to play a role in the cellular response to deprivation-induced plasticity during the CP. For example, in vivo expression of constitutively-active forms of H-ras accelerate ODP and are associated with enhanced LTP (Kaneko et al, 2010), and layer 4 to layer 2/3 theta-burst LTP has been implicated in maintenance of open-eye response potentiation after 6–7d of MD (Smith et al, 2009). Similarly, in cortical injury and infarctinduced plasticity models an increase in theta-burst driven NMDA receptor-dependent LTP (Hagermann et al, 1998, Huemmeke et al, 2004), and impaired layer 2/3 LTD (Imbrosci et al, 2010) are seen approximately 7d after injury.…”