Obligatory Role for the Immediate Early Gene NARP in Critical Period Plasticity

Abstract

SUMMARY The immediate early gene NARP is an AMPAR binding protein that is specifically enriched at excitatory synapses onto fast-spiking parvalbumin-positive interneurons (FS (PV) INs). Here we show that transgenic deletion of NARP decreases the number of excitatory synaptic inputs onto FS (PV) INs, and reduces net excitatory synaptic drive onto FS (PV) INs. Accordingly, the visual cortex NARP −/− mice is hyper-excitable, and unable to express ocular dominance plasticity, although many aspects of visual function are unimpaired. Importantly, the number and strength of inhibitory synaptic contacts from FS (PV) INs onto principle neurons in the visual cortex is normal in NARP −/− mice, and enhancement of this output recovers the expression of experience-dependent synaptic plasticity. Thus the recruitment of inhibition from FS (PV) INs plays a central role in enabling the critical period for ocular dominance plasticity.

Critical periods in amblyopia

“…Several proteins that regulate synaptic strength and/or number are highly enriched at excitatory synapses onto PV interneurons and impact the timing of the critical period and NRG1 (NARP: Chang et al, 2010; Gu et al, 2013, Pelkey et al, 2015; Gu et al, 2016; kaplan et al, 2016; Sun et al, 2016). Accordingly, NARP-deficient mice fail to initiate a critical period unless rescued by enhancing the strength of the inhibitory output or excitatory drive onto PV interneurons (Gu et al, 2013; Gu et al, 2016). …”

Molecular Mechanisms at the Basis of Plasticity in the Developing Visual Cortex: Epigenetic Processes and Gene Programs

“…Additionally, the IEG Narp (neuronal activity regulated pentraxin), which encodes a secreted synaptic protein that can bind to and induce clustering of glutamate AMPA receptors, appears to be involved in phenomena of V1 plasticity during early life. There is evidence that Narp recruits AMPA receptors at excitatory synapses onto Pv+ interneurons to rebalance excitation/inhibition dynamics of neuronal networks after episodes of increased excitability94 and Narp expression seems to play a key role in enabling V1 plasticity during the CP 95…”

Bistable Parvalbumin Circuits Pivotal for Brain Plasticity

“…PV-cell maturation is maintained by a variety of molecules, including neurotrophins (BDNF, GDNF), homeoproteins (Otx2), neuronal pentraxins (NARP) and neuregulin-1 (NRG-1) signaling (Canty et al, 2011; Spatazza et al, 2013; Gu et al, 2013; Tamura et al, 2012). Curiously, these are all non-cell autonomous, activity-dependent factors, further supporting a hub-like role for PV-cells in monitoring the local circuit milieu.…”

“…They further confirm their previous report of robust, long-lasting and reversible increases in the number of mossy fiber filopodial synapses onto PV-cells during learning (Ruediger et al, 2011). This up-regulation of excitatory inputs onto high-PV cells suggests a common role for the pentraxin NARP, which is secreted at excitatory connections and obligatory for critical period plasticity (Gu et al, 2013). In limbic areas, proteolytic processing of NRG-1 by neurops in might further regulate PV-neurons to control neural plasticity (Tanaka et al, 2012).…”