Glycinergic Synapses in Patterned Motor Behaviors

GLYCINERGIC SYNAPSES IN PATTERNED MOTOR BEHAVIORS Patterned motor output is generated in the spinal cord by neuronal circuits made up of excitatory (mostly glutamatergic) and inhibitory (mostly glycinergic) interneurons that synapse both with each other and with motor neurons. The balance between excitatory and inhibitory synapses onto interneurons and motor neurons underlies normal functioning of locomotor circuits that produce rhythmic motor output (Grillner et al., 1995; Hultborn and Nielsen, 2007). In mammals, for example, individual motor neurons coordinate between 20,000 to 50,000 synaptic inputs (Gelfan, 1963; Hochman, 2007). These pre-synaptic inputs align with post-synaptic receptors to determine the duration and frequency with which post-synaptic neurons fi re action potentials. Genetic disruption of glycinergic synapses onto both interneurons and motor neurons results in locomotory dysfunction (Kingsmore et al., 1994; Mulhardt et al., 1994; Gomeza et al., 2003a, b; Cui et al., 2005; Hirata et al., 2005). Such locomotory dysfunction is exhibited by two human genetic diseases, hyperekplexia and glycine encephalopathy. Hyperekplexia is characterized by insuffi cient glycinergic inhibition leading to an excessive startle response (Harvey et al., 2008). Glycine encephalopathy, in contrast, is marked by excess glycinergic inhibition leading to hypotonia and subsequent diffi culties in breathing (Applegarth and Toone, 2006). As a model for genetically inherited diseases of the nervous system, zebrafi sh have signifi cant advantages that compliment existing mammalian models. In particular, compared to mammals, zebrafi sh develop externally over a compressed time scale, facilitating both observations and experimental manipulations to understand The zebrafi sh, Danio rerio, provides a vertebrate animal model of inherited human diseases that impact glycinergic synapse function and plasticity (Oda et al., 1998; Cui et al., 2005; Hirata et al., 2005; Downes and Granato, 2006; Rigo and Legendre, 2006; Mongeon et al., 2008). As the predominant inhibitory neurotransmitter in vertebrate brain stem and spinal cord, glycine is critically important for the generation of rhythmic motor behaviors (Moss and Smart, 2001). Indeed, in humans, rhythmic motor behaviors are disrupted by mutations that either reduce glycinergic signaling in the case of the startle syndrome hyperekplexia (Bakker et al., 2006; Harvey et al., 2008), or augment glycinergic signaling in the case of glycine encephalopathy (Applegarth and Toone, 2006). In patients with glycine encephalopathy, elevated glycine disrupts respiratory circuits so that babies with the disease require a ventilator to breathe (Applegarth and Toone, 2004). With time however, many affected infants recover the ability to breathe on their own, and a small subset of these infants recover normal neurological functions (Boneh et al., 2008), suggesting compensatory or homeostatic mechanisms can reduce the severity of the disease. Variable outcomes in human patients with glycine encephalopathy stand in contrast to 100% motor impairment in the mouse, or 100% motor recovery in the zebrafi sh models of the disease (Gomeza et al., 2003a; Luna et al., 2004). Zebrafi sh, therefore, are ideal models for studying homeostatic mechanisms that can restore motor behaviors. In zebrafi sh, gradual motor recovery is mirrored by reductions in evoked glycinergic post-synaptic potentials. This gradual reduction in the strength of glycinergic signaling culminates with the downregulation of glycine receptor RNA and protein (Mongeon et al., 2008). Still, there are outstanding questions, such as how motor recovery is initiated, and how sequential plasticity mechanisms Glycinergic synapse development, plasticity, and homeostasis in zebrafi sh