Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons.

Minhan Ka,Yeon-Hee Kook,Woo-Yang Kim,Shilpa Buch,Ke Liao

doi:10.1038/cddis.2016.319

Minhan Ka, Yeon-Hee Kook + Show 3 more

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https://doi.org/10.1038/cddis.2016.319

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Abstract

Cocaine is a highly addictive narcotic associated with dendritic spine plasticity in the striatum. However, it remains elusive whether cocaine modifies spines in a cell type-specific or region-specific manner or whether it alters different types of synapses in the brain. In addition, there is a paucity of data on the regulatory mechanism(s) involved in cocaine-induced modification of spine density. In the current study, we report that cocaine exposure differentially alters spine density, spine morphology, and the types of synapses in hippocampal and cortical neurons. Cocaine exposure in the hippocampus resulted in increased spine density, but had no significant effect on cortical neurons. Although cocaine exposure altered spine morphology in both cell types, the patterns of spine morphology were distinct for each cell type. Furthermore, we observed that cocaine selectively affects the density of excitatory synapses. Intriguingly, in hippocampal neurons cocaine-mediated effects on spine density and morphology involved sigma-1 receptor (Sig-1 R) and its downstream TrkB signaling, which were not the case in cortical neurons. Furthermore, pharmacological inhibition of Sig-1 R prevented cocaine-induced TrkB activation in hippocampal neurons. Our findings reveal a novel mechanism by which cocaine induces selective changes in spine morphology, spine density, and synapse formation, and could provide insights into the cellular basis for the cognitive impairment observed in cocaine addicts.

Highlights

We provide evidence that cocaine differentially affects dendritic spine density and morphology in hippocampal versus cortical neurons via the regulation of TrkB signaling
Transactivation of TrkB by sigma-1 receptor (Sig-1 R) has an important role in cocaine-mediated dendritic spine impairment (Figure 8)
We found that cocaine administration alters spine density and morphology, which is involved in the strength and turnover of synapses.[43,44,45,46]

Summary

Introduction

Exposure to cocaine has been shown to interrupt normal cognition and memory, leading to brain malfunction and addiction.[1,2] Most studies involving cocaine administration have focused on the nucleus accumbens (NA), an area of the brain in the ventral striatum that receives rich dopaminergic innervation from the ventral tegmental area (VTA).[3,4] This neural circuit is central to transmitting the reward sensations related to drug addiction.[5,6] there are other brain regions in this circuit, such as the hippocampus and cerebral cortex, that are known to participate in associative processes including learning and memory.[7,8] The hippocampus is directly connected to the NA and VTA, and can contribute to the activity of dopaminergic neurons in the VTA.[9,10] Neurons in the cerebral cortex have a role in dopamine reward circuitry.[11,12]. The number and morphology of dendritic spines can be adjusted in response to activity and experience.[13] Formation of new dendritic spines and elimination or structural modification of existing spines have been proposed as mechanisms of synaptic plasticity, which in turn is involved in learning, memory, and addiction.[14,15] Cocaine administration in rats causes learning and memory deficits,[16,17] suggesting that cocaine could elicit structural changes in hippocampal and/or cortical spines. Received 23.6.16; revised 31.8.16; accepted 09.9.16; Edited by A Verkhratsky mechanism via CaMKII activation of cAMP response elementbinding protein (CREB).[1,29] Rac small GTP-binding proteins are master regulators of actin cytoskeletons and play important roles in the formation of dendritic spines and synapses.[30,31,32,33,34] Interestingly, Rac[1] GTPase is a target of Sig[1] R and mediates dendritic spine formation in hippocampal neurons.[35]. Our findings describe a cell type-specific effect and a new mechanism for cocaine-induced spine plasticity

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Conclusion