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Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition.

Publication ,  Journal Article
Southwell, DG; Seifikar, H; Malik, R; Lavi, K; Vogt, D; Rubenstein, JL; Sohal, VS
Published in: J Neurosci
March 11, 2020

Manipulations that enhance GABAergic inhibition have been associated with improved behavioral phenotypes in autism models, suggesting that autism may be treated by correcting underlying deficits of inhibition. Interneuron transplantation is a method for increasing recipient synaptic inhibition, and it has been considered a prospective therapy for conditions marked by deficient inhibition, including neuropsychiatric disorders. It is unknown, however, whether interneuron transplantation may be therapeutically effective only for conditions marked by reduced inhibition, and it is also unclear whether transplantation improves behavioral phenotypes solely by normalizing underlying circuit defects. To address these questions, we studied the effects of interneuron transplantation in male and female mice lacking the autism-associated gene, Pten, in GABAergic interneurons. Pten mutant mice exhibit social behavior deficits, elevated synaptic inhibition in prefrontal cortex, abnormal baseline and social interaction-evoked electroencephalogram (EEG) signals, and an altered composition of cortical interneuron subtypes. Transplantation of wild-type embryonic interneurons from the medial ganglionic eminence into the prefrontal cortex of neonatal Pten mutants rescued social behavior despite exacerbating excessive levels of synaptic inhibition. Furthermore, transplantation did not normalize recipient EEG signals measured during baseline states. Interneuron transplantation can thus correct behavioral deficits even when those deficits are associated with elevated synaptic inhibition. Moreover, transplantation does not exert therapeutic effects solely by restoring wild-type circuit states. Our findings indicate that interneuron transplantation could offer a novel cell-based approach to autism treatment while challenging assumptions that effective therapies must reverse underlying circuit defects.SIGNIFICANCE STATEMENT Imbalances between neural excitation and inhibition are hypothesized to contribute to the pathophysiology of autism. Interneuron transplantation is a method for altering recipient inhibition, and it has been considered a prospective therapy for neuropsychiatric disorders, including autism. Here we examined the behavioral and physiological effects of interneuron transplantation in a mouse genetic model of autism. They demonstrate that transplantation rescues recipient social interaction deficits without correcting a common measure of recipient inhibition, or circuit-level physiological measures. These findings demonstrate that interneuron transplantation can exert therapeutic behavioral effects without necessarily restoring wild-type circuit states, while highlighting the potential of interneuron transplantation as an autism therapy.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

March 11, 2020

Volume

40

Issue

11

Start / End Page

2215 / 2227

Location

United States

Related Subject Headings

  • Synapses
  • Social Behavior
  • Random Allocation
  • Prefrontal Cortex
  • Phenotype
  • Patch-Clamp Techniques
  • PTEN Phosphohydrolase
  • Neurology & Neurosurgery
  • Neural Inhibition
  • Mice, Knockout
 

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Southwell, D. G., Seifikar, H., Malik, R., Lavi, K., Vogt, D., Rubenstein, J. L., & Sohal, V. S. (2020). Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition. J Neurosci, 40(11), 2215–2227. https://doi.org/10.1523/JNEUROSCI.1063-19.2019
Southwell, Derek G., Helia Seifikar, Ruchi Malik, Karen Lavi, Daniel Vogt, John L. Rubenstein, and Vikaas S. Sohal. “Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition.J Neurosci 40, no. 11 (March 11, 2020): 2215–27. https://doi.org/10.1523/JNEUROSCI.1063-19.2019.
Southwell DG, Seifikar H, Malik R, Lavi K, Vogt D, Rubenstein JL, et al. Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition. J Neurosci. 2020 Mar 11;40(11):2215–27.
Southwell, Derek G., et al. “Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition.J Neurosci, vol. 40, no. 11, Mar. 2020, pp. 2215–27. Pubmed, doi:10.1523/JNEUROSCI.1063-19.2019.
Southwell DG, Seifikar H, Malik R, Lavi K, Vogt D, Rubenstein JL, Sohal VS. Interneuron Transplantation Rescues Social Behavior Deficits without Restoring Wild-Type Physiology in a Mouse Model of Autism with Excessive Synaptic Inhibition. J Neurosci. 2020 Mar 11;40(11):2215–2227.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

March 11, 2020

Volume

40

Issue

11

Start / End Page

2215 / 2227

Location

United States

Related Subject Headings

  • Synapses
  • Social Behavior
  • Random Allocation
  • Prefrontal Cortex
  • Phenotype
  • Patch-Clamp Techniques
  • PTEN Phosphohydrolase
  • Neurology & Neurosurgery
  • Neural Inhibition
  • Mice, Knockout