Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders

Annalisa Nobili, Paraskevi Krashia, Alberto Cordella, Livia La Barbera, Maria Concetta Dell’Acqua, Angela Caruso, Annabella Pignataro, Ramona Marino, Francesca Sciarra, Filippo Biamonte, Maria Luisa Scattoni, Martine Ammassari-Teule, Francesco Cecconi, Nicola Berretta, Flavio Keller, Nicola Biagio Mercuri, Marcello D’Amelio

Research output: Contribution to journalArticlepeer-review

Abstract

Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra+/−) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1+/− females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)7921-7940
Number of pages20
JournalMolecular Neurobiology
Volume55
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • Ambra1
  • Hippocampus
  • Inhibition/excitation ratio
  • Neurodevelopmental disorders
  • Parvalbumin interneurons
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

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