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- Title
Cracking Down on Inhibition: Selective Removal of GABAergic Interneurons from Hippocampal Networks.
- Authors
Antonucci, Flavia; Alpár, Alán; Kacza, Johannes; Caleo, Matteo; Verderio, Claudia; Giani, Alice; Martens, Henrik; Chaudhry, Farrukh A.; Allegra, Manuela; Grosche, Jens; Michalski, Dominik; Erck, Christian; Hoffmann, Anke; Harkany, Tibor; Matteoli, Michela; Härtig, Wolfgang
- Abstract
Inhibitory(GABAergic)interneuronsentrainassembliesofexcitatoryprincipalneuronstoorchestrateinformationprocessinginthehippocampus. 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/systemAtransporter 1+, somatostatin +, vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB1 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 identifySAVAsas 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.
- Subjects
GABA; INTERNEURONS; HIPPOCAMPUS (Brain); SPASMS; LABORATORY rats; NEURAL transmission
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 6, p1989
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2720-11.2012