Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Philipp Eckert; Philine Marchetta; Marie K Manthey; Michael H Walter; Sasa Jovanovic; Daria Savitska; Wibke Singer; Michele H Jacob; Lukas Rüttiger; Thomas Schimmang; Ivan Milenkovic; Peter K D Pilz; Marlies Knipper

doi:10.3389/fnmol.2021.642679

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Front Mol Neurosci. 2021 Mar 26:14:642679. doi: 10.3389/fnmol.2021.642679. eCollection 2021.

Authors

Affiliations

¹ Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, University of Tübingen, Tübingen, Germany.
² Department of Neuroscience, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States.
³ Department for Animal Physiology, Institute of Neurobiology, University of Tübingen, Tübingen, Germany.
⁴ School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
⁵ Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, Valladolid, Spain.

Abstract

Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of Bdnf ^Pax2 KOs causes severe cognitive disabilities. In Bdnf ^Pax2 KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing Bdnf ^Pax2 KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

Keywords: Arc/Arg3.1; BDNF; GABAergic interneuron; Pax2; autism spectrum disorder; parvalbumin interneuron.

Grants and funding

R01 MH106623/MH/NIMH NIH HHS/United States