In Vivo Cocaine Experience Generates Silent Synapses

Abstract

Summary Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated post-developmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B–containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

“…In NAc shell MSNs, laser stimulation (467 μm, 0.1-1 ms) evoked EPSCs, which were presumably from ChR2-expressing PVT-to-NAc synapses. A minimal stimulation assay (Isaac et al, 1995;Liao et al, 1995;Huang et al, 2009) revealed that silent synapse levels were significantly increased within this projection (Figure 2a-c; t(25) = 2.69, po0.05, saline 21.27 ± 8.08%, cocaine 47.03 ± 5.60%). We also noted that the basal (saline) levels of silent synapses (~20%) appear to be higher in this projection than other NAc projections (o10%) previously examined in age-matched rats Ma et al, 2014).…”

“…We thus measured the ratio of the amplitudes of AMPAR-and NMDAR-mediated EPSCs at PVT-to-NAc synapses. AMPAR EPSCs were optogenetically elicited (stimulation duration, 0.1-1.5 ms) at − 70 mV, while NMDAR EPSCs were elicited at +50 mV with the current amplitude 40 ms after the current peak defined as the amplitude of NMDAR EPSCs (at this time point, minimal AMPAR-mediated components are active) (Huang et al, 2009). One-to-2 days after cocaine selfadministration, the AMPAR/NMDAR ratio was significantly decreased (Figure 2d and e; t(11) = 2.53, po0.05, saline 2.21 ± 0.69, cocaine 0.58 ± 0.09), consistent with the above results, indicating that the portion of NMDAR-only synapses is significantly increased.…”

“…Structurally, the density of dendritic spines, the postsynaptic structures of excitatory synapses, is increased after cocaine withdrawal (Robinson and Kolb, 2004). The new spines are thought to be nascent synapses, generated initially as AMPAR-silent synapses after cocaine exposure and mature into AMPAR-present synapses after cocaine withdrawal to remodel the NAc circuits (Huang et al, 2009;Lee and Dong, 2011;Huang et al, 2013;Dong and Nestler, 2014). This notion has been further examined in two limbic projections to the NAc shell, the prefrontal cortical and amygdala projections, in which silent synapses are generated after cocaine self-administration, and a portion of them unsilences to become fully functional synapses by recruiting CP-AMPARs Ma et al, 2014).…”

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Failures and responses at − 75 mV (F − 75 ) and at +40 mV (F +40 ) were identified by visual analysis of traces. The fraction of silent synapses was calculated using an equation: 1 − Ln (F − 75 )/Ln(F +40 ) (Huang et al, 2009). …”

“…Recently, new silent synapses were found in the adult brain after exposure to cocaine (Huang et al, 2009;Koya et al, 2012), trauma (Lo et al, 2011), chronic stress (Suvrathan et al, 2014), or during aging (Sametsky et al, 2010). Their formation involves de novo synaptogenesis and (or) removal of AMPAR from regular synapses (Hanse et al, 2013).…”