Cracking down on inhibition: Selective removal of GABAergic interneurons from hippocampal networks

Flavia Antonucci, Alán Alpár, Johannes Kacza, Matteo Caleo, Claudia Verderio, Alice Giani, Henrik Martens, Farrukh A. Chaudhry, Manuela Allegra, Jens Grosche, Dominik Michalski, Christian Erck, Anke Hoffmann, Tibor Harkany, Michela Matteoli, Wolfgang Härtig

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Abstract

Inhibitory (GABAergic) interneurons entrain assemblies of excitatory principal neurons to orchestrate information processing in the hippocamps. Disrupting the dynamic recruitment as well as the temporally precise activity of interneurons in hippocampal circuitries can manifest in epileptiform seizures, and impact specific behavioral traits. Despite the importance of GABAergic interneurons during information encoding in the brain, experimental tools to selectively manipulate GABAergic neurotransmission are limited. Here, we report the selective elimination of GABAergic interneurons by a ribosome inactivation approach through delivery of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro as well as in the mouse and rat hippocampus in vivo. We demonstrate the selective loss of GABAergic-but not glutamatergic-synapses, reduced GABA release, and a shift in excitation/inhibition balance in mixed cultures of hippocampal neurons exposed to SAVAs.Wealso show the focal and indiscriminate loss of calbindin +, calretinin +, parvalbumin/system A transporter 1 +, somatostatin +, vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB 1 cannabinoid receptor + and neuropeptide Y + local-circuit interneurons upon SAVA microlesions to the CA1 subfield of the rodent hippocampus, with interneuron debris phagocytosed by infiltrating microglia. SAVA microlesions did not affect VGLUT1 + excitatory afferents. Yet SAVA-induced rearrangement of the hippocampal circuitry triggered network hyperexcitability associated with the progressive loss of CA1 pyramidal cells and the dispersion of dentate granule cells. Overall, our data identify SAVAs as an effective tool to eliminate GABAergic neurons from neuronal circuits underpinning high-order behaviors and cognition, and whose manipulation can recapitulate pathogenic cascades of epilepsy and other neuropsychiatric illnesses.

Original languageEnglish
Pages (from-to)1989-2001
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number6
DOIs
Publication statusPublished - Feb 8 2012

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Antonucci, F., Alpár, A., Kacza, J., Caleo, M., Verderio, C., Giani, A., Martens, H., Chaudhry, F. A., Allegra, M., Grosche, J., Michalski, D., Erck, C., Hoffmann, A., Harkany, T., Matteoli, M., & Härtig, W. (2012). Cracking down on inhibition: Selective removal of GABAergic interneurons from hippocampal networks. Journal of Neuroscience, 32(6), 1989-2001. https://doi.org/10.1523/JNEUROSCI.2720-11.2012