Shea Lab Journal Club: SHANK3 controls maturation of social reward circuits in the VTA

SHANK3 controls maturation of social reward circuits in the VTA. Bariselli et al. (2016) Nature Neuroscience doi:10.1038/nn.4319

This is the latest installment of  an ongoing series of capsule summaries of the Shea Lab journal club meetings. We are doing this to actively provoke open discussion of papers we read that are either published in a traditional journal or BioRxiv.

This meeting was attended by members of the Shea and Tollkuhn labs.


Autism spectrum disorders (ASD) are typically marked by disinterest in social engagement. It is widely accepted that mouse models of ASD also commonly show reduced interest in social partners. Neuroscientists who study ASD have a very limited understanding of the neural circuit basis for social disinterest. However, these authors speculate that social interaction may activate brain reward pathways overlapping with those that are activated by other types of reward such as sucrose or drugs abuse. Moreover, they suggest that mutations that cause ASD may alter social behavior by interfering with the function of these pathways. Specifically, this paper focuses on the role of dopamine releasing neurons in the ventral tegmental area (VTA). As someone who’s interested in this topic, I think this is a reasonable and interesting speculation worth investigating.

To test this idea, the authors use viral delivery of shRNA to knock down Shank3 expression in VTA neurons. Shank3 is a scaffolding protein that contributes to the organization of the postsynaptic membrane, and mutations of Shank3 cause Phelan-McDermid syndrome and other ASDs. By comparing properties of these manipulated neurons to neurons in control mice, they show altered synaptic properties and in vivo spontaneous activity. Mice with shank three knockdown in the VTA also show moderate but significant changes in their preference to approach an enclosure containing a social partner versus an empty enclosure. This behavior phenotype may be related to electrophysiological changes they see in VTA neurons, but it is unclear.

Importantly, in Figure 8 the authors attempt to restore preference for social interaction in Shank3 knockdown mice by optogenetically boosting activity in dopamine releasing VTA neurons. Ostensibly, this experiment makes a more direct link between VTA neuron function and sociability. Most of our journal club group was deeply confused by this experiment. According to the manuscript:

“In vivo, we stimulated VTA DA neurons35 during T2 when mice were in close proximity to the social stimulus (Fig. 8e). ShShank3 mice that did not receive optogenetic stimulation showed a reduction in social preference at T2 (Fig. 8f,g). However, phasic stimulation of VTA DA neurons increased social preference during T2 in both scrShank3 and shShank3 mice (Fig. 8f) and increased normalized social preference of shShank3 mice to the levels of the scrShank3 control group (Fig. 8g).”

So if I understand correctly, the experimenters gave the mice an extremely pleasurable blast of dopamine every time they approach the social partner. Perhaps not surprisingly,  all of the mice started hanging around the social partner, irrespective of whether they had Shank3 knockdown. Are we missing something? How is this different from intracranial self stimulation? Aren’t they just conditioning the mice with the reward signal? I’m curious whether this came up in review. For example, did anyone suggest they try stimulating dopamine release when the mouse approach the empty closure?

I welcome comments from readers and the authors. Maybe there’s something I don’t understand.



2 thoughts on “Shea Lab Journal Club: SHANK3 controls maturation of social reward circuits in the VTA

  1. We would like to thank the Shea lab for their comments.
    In our work we show that by rescuing the synaptic deficits onto DA neurons in the VTA, we ameliorate both neuronal activity and social deficits observed in the Shank3-VTA model. These experiments indicate therefore a causal link between synaptic, activity and behavioral deficits.
    In the optogenetic experiments, we stimulated DA neurons when the mice were in the close proximity of the social encounter. We agree with your comments that we conditioned the mice with the reward signal. We concluded from our results that although the activity of DA neuron decreased as consequence of Shank3 downregulation, these neurons can be stimulated and this stimulation is sufficient to promote social behaviors.

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