ORIGINAL RESEARCH article

Front. Cell. Neurosci.

Sec. Cellular Neuropathology

Volume 19 - 2025 | doi: 10.3389/fncel.2025.1597131

PTEN in somatostatin neurons regulates fear and anxiety and is required for inhibitory synaptic connectivity within central amygdala

Provisionally accepted
Timothy  W HolfordTimothy W HolfordKaitlyn  LetourneauKaitlyn LetourneauCarolyn  Von-WalterCarolyn Von-WalterCody  LoomisCody LoomisDaniela  MoncaleanoDaniela MoncaleanoM. McLean  BoltonM. McLean Bolton*
  • Max Planck Florida Institute for Neuroscience (MPFI), Jupiter, United States

The final, formatted version of the article will be published soon.

The PTEN phosphatase is a negative regulator of the mTOR pathway and is strongly associated with Autism Spectrum Disorder (ASD), with up to 25% of ASD patients with macrocephaly harboring PTEN mutations. Mice with germline PTEN haploinsufficiency show behavioral characteristics resembling ASD, as do various mouse models with conditional knockouts of PTEN. Human tissue studies and those from multiple genetic mouse models suggest that dysfunction of GABAergic interneurons may play a role in the development of ASD, but the precise mechanisms remain elusive. PTEN provides a target for investigation because it regulates the development of inhibitory neurons arising from the medial ganglionic eminence, promoting the survival and maturation of parvalbumin (PV+) neurons at the expense of somatostatin (SOM+) neurons. Here, we investigate how PTEN regulates SOM+ neurons at the cellular and circuit level in the central lateral amygdala (CeL), an area that governs the key ASD behavioral symptoms of social anxiety and altered emotional motivation for social engagement. Using 2-photon local circuit mapping, we found that knocking out PTEN in SOM+ neurons decreases CeL local circuit connectivity. Specifically, this manipulation decreased the strength of connections between individual neurons and altered the distribution of local connections in a cell-type specific manner. In contrast to the deficit in local inhibitory connections within CeL, the excitatory drive from the major CeL input, the basolateral amygdala (BLA) was enhanced. This combined imbalance of enhanced excitation and diminished inhibition likely underlies the heightened fear learning and anxiety we observed in the PTEN-SOM-KO mice.

Keywords: Autism1, amygdala2, pten3, inhibitory neurons4, circuit mapping5, synaptic transmission6, two photon microscopy7. (Min

Received: 20 Mar 2025; Accepted: 02 Jun 2025.

Copyright: © 2025 Holford, Letourneau, Von-Walter, Loomis, Moncaleano and Bolton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: M. McLean Bolton, Max Planck Florida Institute for Neuroscience (MPFI), Jupiter, United States

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