Oxytocin Restores Social Memory in Two Different Autism Mouse Models Through a Specific Brain Region

What the researchers found

Two different autism spectrum disorder (ASD) mouse models were used. One was created by prenatal valproic acid exposure (environmental cause), the other by the Nl3R451C genetic mutation (genetic cause). Both had impaired social memory, the ability to distinguish familiar from novel mice.

Selectively expressing hM3Dq (an activating DREADD receptor) in oxytocin receptor-positive (OXTR+) neurons in the lateral septum (LS) allowed researchers to activate these specific neurons with a chemical trigger.

In the valproic acid model, activation restored social memory in the three-chamber social test. In the Nl3R451C model, social memory was restored in a single-field test. Both represent core ASD symptoms.

The OXTR+ neurons in the LS project to the CA1 region of the hippocampus, suggesting social memory depends on an oxytocin-responsive circuit from the lateral septum to the hippocampus. This identifies a specific neural pathway that could explain how intranasal oxytocin therapy improves social symptoms in ASD patients.

Why it matters

Oxytocin nasal spray has shown promise in ASD clinical trials, but nobody knew exactly where in the brain it works. This study identifies the lateral septum's OXTR+ neurons as a critical node. Targeting this specific circuit could lead to more precise therapies for the social symptoms of autism.

The numbers in context

2 ASD models; OXTR+ LS neurons; social memory restored; LS→CA1 projection; DREADDs used

How the study worked

Neuroscience study using two mouse models of ASD. DREADDs (designer receptors exclusively activated by designer drugs) were virally expressed in OXTR+ neurons of the lateral septum. Social memory was tested before and after neuron activation. Neural projection mapping confirmed LS-to-CA1 connectivity.

Who was studied

Two ASD mouse models: VPA-exposed and Nl3R451C knock-in

What this study cannot tell us

Mouse models of autism have limited translational validity. The social behaviors tested are simplified proxies for human social cognition. DREADDs provide proof of concept but are not a practical therapy. The two mouse models represent only a fraction of ASD causes. Whether the LS-CA1 circuit functions the same way in the human brain is unknown.

How to read the evidence

Moderate evidence from well-designed animal neuroscience experiments. The circuit is convincingly mapped, but mouse social behavior has limited translation to human ASD.

When this study was published

Published in 2020. Oxytocin for ASD remains under active clinical investigation with mixed human trial results.

The bigger picture

Oxytocin nasal spray has shown promise in ASD clinical trials, but nobody knew where in the brain it works. Identifying the lateral septum's OXTR+ neurons as a critical node could guide more targeted therapies and help predict which patients will respond.

Questions still open

• Can the lateral septum be specifically targeted by intranasal oxytocin in humans?
• Does this circuit also mediate other social behaviors impaired in ASD?
• Would human fMRI studies show lateral septum activation correlating with oxytocin response?

Common questions

Read the original research

Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models.

Scientific reports, 10(1), 22173

Citation

Horiai, Machi; Otsuka, Ayano; Hidema, Shizu; Hiraoka, Yuichi; Hayashi, Ryotaro; Miyazaki, Shinji; Furuse, Tamio; Mizukami, Hiroaki; Teruyama, Ryoichi; Tamura, Masaru; Bito, Haruhiko; Maejima, Yuko; Shimomura, Kenju; Nishimori, Katsuhiko. (2020). Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models.. Scientific reports, 10(1), 22173. https://doi.org/10.1038/s41598-020-79109-0