Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome

Larisa V Lysenko; Jeesun Kim; Francisco Madamba; Anna A Tyrtyshnaia; Aarti Ruparelia; Alexander M Kleschevnikov

doi:10.1016/j.nbd.2018.03.005

Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome

Neurobiol Dis. 2018 Jul:115:1-8. doi: 10.1016/j.nbd.2018.03.005. Epub 2018 Mar 14.

Authors

Larisa V Lysenko¹, Jeesun Kim², Francisco Madamba², Anna A Tyrtyshnaia³, Aarti Ruparelia², Alexander M Kleschevnikov⁴

Affiliations

¹ Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States; Academy of Biology and Biotechnology of Southern Federal University, 194/1 Stachki Ave, Rostov-na-Donu 344090, Russian Federation.
² Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States.
³ Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States; School of Biomedicine, Far Eastern Federal University, Sukhanova 8, Vladivostok 690950, Russian Federation.
⁴ Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093, CA, United States; School of Biomedicine, Far Eastern Federal University, Sukhanova 8, Vladivostok 690950, Russian Federation. Electronic address: akleschevnikov@ucsd.edu.

PMID: 29550538
DOI: 10.1016/j.nbd.2018.03.005

Abstract

Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABA_A agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS.

Keywords: Acute slices; Developmental excitatory-to-inhibitory GABA switch; Down syndrome; GDP; Giant depolarizing potentials; Hippocampus; MUA; Multi-unit activity; Neural circuits; Primary cultures.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Action Potentials / physiology*
Animals
Cells, Cultured
Down Syndrome / genetics*
Down Syndrome / physiopathology
Hippocampus / drug effects
Hippocampus / physiology
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Transgenic
Models, Genetic*
Neural Inhibition / physiology*
Organ Culture Techniques
gamma-Aminobutyric Acid / pharmacology
gamma-Aminobutyric Acid / physiology*

Substances

gamma-Aminobutyric Acid