Real-time prefrontal cortex circuit intervention rescues social behavioral deficits in a genetic model of autism
Abstract/Contents
- Abstract
- Increased cellular excitation/inhibition (E:I) balance has been suggested to represent a neural circuit activity-based final common pathway contributing to social-behavior deficits in autism-spectrum disease. For this hypothesis to be of translational significance, it should be demonstrated that acutely reducing E:I cellular balance can correct social behavior deficits. However, this crucial demonstration has not been possible in any preclinical or clinical model of autism, since currently-available drugs directly affect both excitatory and inhibitory neurons and thus cannot precisely modulate E:I balance. Even more fundamentally, it is not clear when such an intervention would have to be delivered, since if the initial maladaptive E:I balance pathology is exerted early in development, interventions delivered later could be ineffective. Here, we directly explore these questions, beginning with validated clinically-guided mice genotypically based on the human-pedigree CNTNAP2 mutation (showing social behavior deficits and stereotyped/repetitive behaviors with hyperactivity at baseline). Mice lacking CNTNAP2 gene have decreased number of parvalbumin and oxytocin neruons, as well as cortical developmental abnormalities. We achieved temporally-precise and cell-specific reduction of medial prefrontal cortex (mPFC) E:I balance by both selectively increasing the excitability of inhibitory parvalbumin (PV) neurons and decreasing the excitability of excitatory pyramidal (PYR) neurons using optogenetic approaches. Surprisingly, this real-time and reversible E:I balance modulation acutely rescued social behavior deficits and hyperactivity when delivered in the adult brain. Delving into possible mechanisms, we discovered (using fiber photometry technology to record naturally-occurring cell- specific activity signals during free behavior) that native PV neuron dynamics differed between CNTNAP2 knockout (KO) and wild-type (WT) mice in mPFC. While in WT animals the inhibitory PV cells encoded social interaction via increased activity (compared to the level in novel-object interactions), in KO animals the PV neurons failed to increase this inhibitory activity in social vs. other types of interaction. We then investigated the role of neuromodulation in mPFC on social behaviors. We found that infusion of oxytocin receptor antagonists into mPFC reduced social interactions in WT mice. More interestingly, oxytocin receptor agonist infusion rescued social behavior deficits and hyperactivity in CNTNAP2 KO mice, while not causing a significant change in WT social interactions. Together, these results demonstrate the significance of real-time mPFC E:I cellular modulation in social behavior and in rescuing autism-related symptomatology, highlighting the promise of circuit-based mechanisms and translational targets for autism.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Selimbeyoglu, Aslihan |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Deisseroth, Karl |
| Thesis advisor | Deisseroth, Karl |
| Thesis advisor | Luo, Liqun, 1966- |
| Thesis advisor | Malenka, Robert C |
| Thesis advisor | Shen, Kang, 1972- |
| Advisor | Luo, Liqun, 1966- |
| Advisor | Malenka, Robert C |
| Advisor | Shen, Kang, 1972- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Aslihan Selimbeyoglu. |
|---|---|
| Note | Submitted to the Program in Neuroscience. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Aysel Aslihan Selimbeyoglu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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