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.
Highlights
Neuronal cell death is a necessary process that is essential for the developmental refinement of complex neural networks
To check that GAD67 was responsible for GABA synthesis within the developing spinal cord, we measured the amount of GABA in the cervical and lumbar regions of E18.5 spinal cords from GAD67-deficient mice compared to their wild type littermates
This data shows that the drop in GABA content within the developing spinal cord was reduced by the same amount to that previously reported for the brain in mice lacking GAD67 [2,34]
Summary
Neuronal cell death is a necessary process that is essential for the developmental refinement of complex neural networks. Fewer motor neurons survive through the cell death period when muscle activity is experimentally increased, possibly due to reduced access to trophic factors resulting from fewer formed neuromuscular synapses [1,11]. These observations have led to the idea that muscle electrical activity evoked by neuromuscular synaptic activity is the regulator of motor neuron numbers during developmental cell death. This is thought to constitute an intrinsic safety mechanism that adjusts the number of surviving motor neurons innervating a given muscle to the needs of the muscle for complete and effective control at birth [6,12,13,14,15]
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