Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Abstract

Smoking is the leading cause of preventable death in the United States and success rates for quitting remain low. High relapse rates are attributed to pervasive nicotine-reinforced associative learning of incentive cues that is highly resistant to extinction. Why such learning is so persistent is poorly understood but may arise as a consequence of neuroadaptations in synaptic plasticity induced by chronic nicotine. We used whole-cell patch clamp recording to investigate the effect of chronic nicotine (cNIC) on synaptic plasticity in dopamine D2 receptor-expressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited long-term potentiation in response to high-frequency stimulation instead of the expected depression. cNIC decreased baseline AMPA/NMDA ratio, arising from increased NMDA currents enriched in the NR2B subunit with a concomitant upregulation of NMDA-only, silent synapses. These data demonstrate that cNIC can increase silent synapses in MSNs, as observed with cocaine and opiates, and alter the regulation of corticostriatal plasticity. Prior work has characterized cocaine- and morphine-induced upregulation of silent synapses in the ventral striatum; we show it can occur in the dorsal striatum, a region associated with later stages of addiction, craving, and cue-induced relapse.

Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

“…Our laboratory was the first to show functional evidence that LDT neurons of juvenile mice display silent synapses (Figure 2), and, further, that PNE treatment has an impact on their expression. While no differences were seen in silent synapses in cholinergic neurons following PNE treatment, an increased number of silent synapses were seen in putative GABAergic LDT neurons, which parallels the enhanced silent synapses seen in inhibitory NAc neurons following postnatal drug administration (Xia et al, 2017). The higher number of silent synapses seen in putative GABAergic LDT neurons associated with PNE treatment provides indirect support of the interpretation that PNE is associated with a delayed maturation of glutamate synapses in these inhibitory neurons.…”

“…However, their appearance or activation upon drug exposure can be dependent on many factors. Acute nicotine application in hippocampal brain slices of newborn rats can activate silent synapses in CA1 neurons, whereas, chronic nicotine exposure in mice was associated with increased number of silent synapses in medium spiny neurons of the striatum (Maggi et al, 2003;Xia et al, 2017), suggesting that the outcomes of nicotine-induced alterations, and perhaps also of other drugs, on silent synapses likely depends on brain areas, drug concentration, and developmental phase at which drug exposure occurs. When taken together, silent synapses represent a powerful mechanism of metaplasticity in the brain, that can be either generated or unsilenced in a region-specific, age-dependent fashion and which appear to be dynamically controlled by drugs of abuse, which likely importantly contribute to drug-induced remodeling of reward-related circuits (Abraham and Bear, 1996;Brown et al, 2011;Lee et al, 2013;Huang et al, 2015;Dong, 2016).…”

“…Exposure to drugs of abuse has been shown to reactivate plasticity mechanisms seen during development in addictionassociated brain regions, which may play a role in the formation of addiction-related memories (Dong and Nestler, 2014) as reactivation of silent synapses remodels brain circuits and alters behavior, including those which are addiction-related (Brown et al, 2011;Lee et al, 2013). Higher rates of silent synapses in the rodent brain have been associated with cocaine, alcohol, nicotine, and morphine administration, which was an effect found mostly in NAc GABAergic populations (Huang et al, 2009;Graziane et al, 2016;Xia et al, 2017;Beroun et al, 2018). Our laboratory was the first to show functional evidence that LDT neurons of juvenile mice display silent synapses (Figure 2), and, further, that PNE treatment has an impact on their expression.…”

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction

“…Moreover, NMDAR signaling is also closely related to synaptic plasticity, such as LTP and LTD, spatial aspects of episodic memory and addiction, due to their unique composition, dynamic expression, trafficking, and endocytosis. Chronic nicotine exposure, cocaine administration, and morphine administration all result in the upregulation of silent synapses that contain NMDARs with enriched NR2B subunits but no AMPARs . Some molecular mechanisms are verified, for example, BDNF‐mediated suppression of cocaine‐seeking involved an interaction of Src family kinases (SFKs), tyrosine kinase receptors (TrKBs), and NMDARs.…”

“…www.advancedsciencenews.com www.bioessays-journal.com in the upregulation of silent synapses that contain NMDARs with enriched NR2B subunits but no AMPARs. [105][106][107][108] Some molecular mechanisms are verified, for example, BDNFmediated suppression of cocaine-seeking involved an interaction of Src family kinases (SFKs), tyrosine kinase receptors (TrKBs), and NMDARs. SFKs phosphorylate NMDAR subunits, which may sustain ERK activation following TrKB activation via Zn 2+ that influxes through NMDAR channels.…”