Search for: All records

Neurological difficulties commonly accompany individuals suffering from congenital disorders of glycosylation, resulting from defects in the N-glycosylation pathway. Vacant N-glycosylation sites (N220 and N229) of Kv3, voltage-gated K+ channels of high-firing neurons, deeply perturb channel activity in neuroblastoma (NB) cells. Here we examined neuron development, localization, and activity of Kv3 channels in wildtype AB zebrafish and CRISPR/Cas9 engineered NB cells, due to perturbations in N-glycosylation processing of Kv3.1b. We showed that caudal primary (CaP) motor neurons of zebrafish spinal cord transiently expressing fully glycosylated (WT) Kv3.1b have stereotypical morphology, while CaP neurons expressing partially glycosylated (N220Q) Kv3.1b showed severe maldevelopment with incomplete axonal branching and extension around the ventral musculature. Consequently, larvae expressing N220Q in CaP neurons had impaired swimming locomotor activity. We showed that replacement of complex N-glycans with oligomannose attached to Kv3.1b and at cell surface lessened Kv3.1b dispersal to outgrowths by altering the number, size, and density of Kv3.1b-containing particles in membranes of rat neuroblastoma cells. Opening and closing rates were slowed in Kv3 channels containing Kv3.1b with oligomannose, instead of complex N-glycans, which suggested a reduction in the intrinsic dynamics of the Kv3.1b α-subunit. Thus, N-glycosylation processing of Kv3.1b regulates neuronal development and excitability, thereby controlling motor activity. 

Social status-dependent modulation of neural circuits has been investigated extensively in vertebrate and invertebrate systems. However, the effects of social status on neuromodulatory systems that drive motor activity are poorly understood. Zebrafish form a stable social relationship that consists of socially dominant and subordinate animals. The locomotor behavior patterns differ according to their social ranks. The sensitivity of the Mauthner startle escape response in subordinates increases compared to dominants while dominants increase their swimming frequency compared to subordinates. Here, we investigated the role of the endocannabinoid system (ECS) in mediating these differences in motor activities. We show that brain gene expression of key ECS protein pathways are socially regulated. Diacylglycerol lipase (DAGL) expression significantly increased in dominants and significantly decreased in subordinates relative to controls. Moreover, brain gene expression of the cannabinoid 1 receptor (CB 1 R) was significantly increased in subordinates relative to controls. Secondly, increasing ECS activity with JZL184 reversed swimming activity patterns in dominant and subordinate animals. JZL184 did not affect the sensitivity of the startle escape response in dominants while it was significantly reduced in subordinates. Thirdly, blockage of CB 1 R function with AM-251 had no effect on dominants startle escape response sensitivity, but startle sensitivity was significantly reduced in subordinates. Additionally, AM-251 did not affect swimming activities in either social phenotypes. Fourthly, we demonstrate that the effects of ECS modulation of the startle escape circuit is mediated via the dopaminergic system specifically via the dopamine D1 receptor. Finally, our empirical results complemented with neurocomputational modeling suggest that social status influences the ECS to regulate the balance in synaptic strength between excitatory and inhibitory inputs to control the excitability of motor behaviors. Collectively, this study provides new insights of how social factors impact nervous system function to reconfigure the synergistic interactions of neuromodulatory pathways to optimize motor output.