Genetic deficiency of GABA differentially regulates respiratory and non-respiratory motor neuron development

PLoS One. 2013;8(2):e56257. doi: 10.1371/journal.pone.0056257. Epub 2013 Feb 15.

Abstract

Central nervous system GABAergic and glycinergic synaptic activity switches from postsynaptic excitation to inhibition during the stage when motor neuron numbers are being reduced, and when synaptic connections are being established onto and by motor neurons. In mice this occurs between embryonic (E) day 13 and birth (postnatal day 0). Our previous work on mice lacking glycinergic transmission suggested that altered motor neuron activity levels correspondingly regulated motor neuron survival and muscle innervation for all respiratory and non respiratory motor neuron pools, during this period of development [1]. To determine if GABAergic transmission plays a similar role, we quantified motor neuron number and the extent of muscle innervation in four distinct regions of the brain stem and spinal cord; hypoglossal, phrenic, brachial and lumbar motor pools, in mice lacking the enzyme GAD67. These mice display a 90% drop in CNS GABA levels ( [2]; this study). For respiratory-based motor neurons (hypoglossal and phrenic motor pools), we have observed significant drops in motor neuron number (17% decline for hypoglossal and 23% decline for phrenic) and muscle innervations (55% decrease). By contrast for non-respiratory motor neurons of the brachial lateral motor column, we have observed an increase in motor neuron number (43% increase) and muscle innervations (99% increase); however for more caudally located motor neurons within the lumbar lateral motor column, we observed no change in either neuron number or muscle innervation. These results show in mice lacking physiological levels of GABA, there are distinct regional changes in motor neuron number and muscle innervation, which appear to be linked to their physiological function and to their rostral-caudal position within the developing spinal cord. Our results also suggest that for more caudal (lumbar) regions of the spinal cord, the effect of GABA is less influential on motor neuron development compared to that of glycine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Stem / cytology*
  • Brain Stem / growth & development
  • Brain Stem / metabolism
  • Cell Count
  • Cell Size
  • Cell Survival
  • Female
  • Gene Deletion
  • Glutamate Decarboxylase / genetics*
  • Glutamate Decarboxylase / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Motor Neurons / cytology
  • Motor Neurons / physiology*
  • Muscles / innervation*
  • Spinal Cord / cytology*
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism
  • gamma-Aminobutyric Acid / genetics*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1

Grant support

The work was funded by project grant 568680 from NHMRC to PGN and MCB, and by a MNDRI project grant to PGN. KLS was supported by postgraduate scholarship from the University of Queensland, and MJF was supported by and APA Scholarship from the Australian Government. YY was supported by a Grant-in aid for scientific research on innovative areas “Mesoscopic Neurocircuitry” and scientific research (B) from MEXT, Japan and Takeda Science Foundation. An ARC LIEF grant LE100100074 funded the stereology system. The authors declare no financial or commercial ties to the production or interpretation of this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.