Academic journal article Genetics

Regulation of Glutamate Signaling in the Sensorimotor Circuit by CASY-1a/calsyntenin in Caenorhabditis Elegans

Academic journal article Genetics

Regulation of Glutamate Signaling in the Sensorimotor Circuit by CASY-1a/calsyntenin in Caenorhabditis Elegans

Article excerpt

BEHAVIORAL output of an organism depends on the combined activity of multiple neural networks in which individual circuits are either activated or inhibited by the action of neurotransmitters or modified through neuropeptides. Locomotion is a very basic yet complex behavior in most organisms. An in-depth understanding of the Caenorhabditis elegans neural connectome provides an excellent model with which to understand the complex molecular and cellular mechanisms operating in locomotory circuits. Neural circuits that produce coordinated dorso-ventral sinusoidal bends allow for normal locomotion in C. elegans. Locomotory behavior is synchronized at multiple levels and involves the integration of diverse sensory cues that are processed by the interneurons and ultimately cause changes at the neuromuscular junctions (NMJ) (de Bono and Maricq 2005; Bargmann 2012). At the C. elegans NMJ, cholinergic motor neurons stimulate muscle contraction as well as activate GABAergic motor neurons that inhibit contraction of the contralateral muscles (White et al. 1986; Alfonso etal. 1993; McIntire etal. 1993a,b; Duerr etal. 2008). Despite an extensive understanding of the development and functioning of the ventral cord motor neurons, the mechanisms controlling motor coordination are still elusive. In mammals, disruption in this motor activity synchronization results in an excitation-inhibition imbalance that has been implicated in several neurological disorders like autism and epilepsy (Fetissov et al. 2003; Lerner et al. 2008; Wu et al. 2011). The C. elegans NMJ provides an excellent model to understand the genetic factors that coordinates this balance, thus providing deeper understanding of the pathogenesis of these disorders.

C. elegans CASY-1 is an ortholog of mammalian calsyntenin genes. Calsyntenins are Cadherin superfamily type-I transmembrane proteins characterized by the presence of two cadherin-like tandem repeats, an LG/LNS domain in the extracellular region, and an intracellular region that carries two kinesin light-chain binding domains (Hintsch et al 2002; Araki et al. 2003, 2004). All these regions are conserved in the C. elegans calsyntenin ortholog, casy-1. Mammals have three calsyntenin genes (clstnl, clstn2, and clstn3) that are highly enriched in the nervous system (Hintsch et al. 2002). Similarly, C. elegans CASY-1 expression is also observed in most head neurons and some other tissues like intestine and gonadal sheath cells (Ikeda et al. 2008; Hoerndli et al. 2009). Polymorphisms of the human clstn2 allele have been associated with increased episodic memory performance (Preuschhof et al. 2010). C. elegans casy-1 has also been reported to be required for memory formation, thus suggesting conservation of functions (Ikeda et al. 2008; Hoerndli et al. 2009). Mammalian clstn3 regulates excitatory and inhibitory synapse development in mice (Pettem etal. 2013; Um etal. 2014), while clstnl acts as a kinesin-1 adaptor that regulates trafficking and processing of amyloid precursor proteins (Konecna et al. 2006; Araki et al. 2007; Steuble et al. 2012; Vagnoni et al. 2012). Calsyntenins are also considered biomarkers for several age-related neurological disorders (Araki et al. 2003; Vagnoni et al. 2012; Uchida et al. 2013). Alterations in calsyntenin expression and function in neurological disorders make them potential candidates that can be explored further at the molecular and physiological levels for their potential roles in the pathogenesis of diseases.

In this study, we are proposing a novel neuromodulatory role of CASY-1-dependent signaling in the regulation of motor circuit dynamics and locomotion. We show that the CASY-1A isoform functions in the sensory neurons to inhibit the activity of command interneurons, thus negatively regulating motor circuit activity and locomotion. The CASY-1A isoform does this by controlling the release of glutamate from glutamatergic sensory neurons. Together, our results support a crucial role of CASY-1 in regulating locomotion dynamics by modulating the activity of the sensorimotor circuit. …

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