Inhibitory Synaptic Influences on Developmental Motor Disorders

Abstract

During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to discuss the differences in limb and respiratory neuromotor control. We then investigate the influences that GABAergic and glycinergic neurotransmission has on two major developmental neuromotor disorders: Rett syndrome and spastic cerebral palsy. We present these two syndromes in order to contrast the approaches to disease mechanism and therapy. While both conditions have motor dysfunctions at their core, one condition Rett syndrome, despite having myriad symptoms, has scientists focused on the breathing abnormalities and their alleviation-to great clinical advances. By contrast, cerebral palsy remains a scientific quagmire or poor definitions, no widely adopted model and a lack of therapeutic focus. We conclude that the sheer abundance of diversity of inhibitory neurotransmitter targets should provide hope for intractable conditions, particularly those that exhibit broad spectra of dysfunction-such as spastic cerebral palsy and Rett syndrome.

Keywords: GABA; Rett syndrome; cerebral palsy; glycine; motor neuron; spasticity.

Figure 1

Locomotor and respiratory neuromotor control. In the case of locomotor control, there are corticospinal influences (blue pyramidal neurons) and bulbospinal influences on spinal cord central pattern generators (purple), and inhibitory (red) and excitatory (green) premotor neurons. These segment-level neurons coordinate motor outputs of the ipsilateral and contralateral side via projections. Ipsilateral and contralateral inhibition via circuits formed from recurrent motor axons also provides for coordination within these segments. In the locomotor system, the major inputs to motor neurons (blue neurons innervating skeletal muscle fibres) come from ipsilateral pattern and premotor neurons within the spinal cord segment. For respiratory neuromotor control, pattern generation and premotor excitatory and inhibitory circuits reside primarily in the brainstem, projecting to ipsilateral phrenic motor neurons. There are some segment-level premotor inputs to motor neurons; however, all pattern generation necessary for breathing resides in the brainstem, with a modicum of cortical modulation for a variety of post-inhibitory behaviours (e.g., speech/vocalisation).

Figure 2

GABAergic and glycinergic synapses. GABA (green circles) is synthesized by GAD65 and GAD67 (green arrow) and packaged into synaptic vesicles by VGAT (blue dashed circles). Upon release into the synaptic cleft, GABA is bound by αβ subunit binding sites (green and orange subunits) at GABA-A receptors. γ subunits (yellow) provide the binding sites for modulators such as benzodiazepines. Following release into the synaptic cleft, GABA reuptake occurs presynaptically via GAT1 (green rhomboid) and in astrocytes (orange) via GAT2/3 (checked green rhomboid). GABA-A receptors are structurally maintained by Neuroligin-2 (green bracket). Glycine (pink circles) is synthesized by serine hydroxymethyltransferase (SHMT—pink arrow) and packaged into synaptic vesicles by VGAT. Upon release into the synaptic cleft glycine is bound by α subunit binding sites (pink subunits) at glycine receptors. Following release into the synaptic cleft, Glycine reuptake occurs presynaptically via GlyT2 (pink rhomboid) and in astrocytes via GlyT1/ASC1 (checked pink rhomboid). β glycine receptor subunits (peach) provide the binding sites for gephyrin (orange bracket) in order to structurally maintain the synapse.

Figure 3

Maturation of neuronal chloride transporters. In immature neurons, chloride (Cl⁻, red drops) concentrations are higher intracellularly due to the expression of immature NKCC2 transporter (orange). When the ion pore of GABAergic or glycinergic synapses is opened (green), chloride efflux (red arrow) occurs depolarizing the neuron. In mature neurons, intracellular chloride concentration is low, due to the expression of the mature KCC2 transporter (blue). When the ion pore of GABAergic of glycinergic synapses is opened chloride influx occurs (blue arrow), hyperpolarizing the neuron.