Activity-dependent changes of synapse strength have been extensively characterized at chemical synapses, but the relationship between physiological forms of activity and strength at electrical synapses remains poorly characterized and understood. For mammalian electrical synapses comprising hexamers of connexin36, physiological forms of neuronal activity in coupled pairs have thus far only been linked to long-term depression; activity that results in strengthening of electrical synapses has not yet been identified. The thalamic reticular nucleus (TRN), a central brain area primarily interconnected by electrical synapses, regulates cortical input from and attention to the sensory surround. Here, we show in electrically coupled TRN pairs that tonic spiking in one neuron results in long-term potentiation of electrical synapses with a magnitude of plasticity that alters the functionality of the synapse. Potentiation is expressed asymmetrically, indicating that regulation of connectivity depends on the direction of use. Further, potentiation depends on calcium flux, and we thus propose a calcium-based activity rule for bidirectional plasticity of electrical synapse strength. Because electrical synapses dominate intra-TRN connectivity, these synapses and their activity-dependent modifications are key dynamic regulators of thalamic attention circuitry. More broadly, we speculate that bidirectional modifications of electrical synapses may be a widespread and powerful principle for ongoing, dynamic reorganization of neuronal circuitry across the brain.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, resulting in progressive locomotor dysfunction. Identification of genes required for the maintenance of these neurons should help to identify potential therapeutic targets. However, little is known regarding the factors that render dopaminergic neurons selectively vulnerable to PD. Here, we show that mutants exhibit an age-dependent progressive loss of dopaminergic neurons, along with subsequent locomotor defects and a shortened lifespan. Knockdown of Scarlet specifically within dopaminergic neurons is sufficient to produce this neurodegeneration, demonstrating a unique role for Scarlet beyond its well-characterized role in eye pigmentation. Both genetic and pharmacological manipulation of the kynurenine pathway rescued loss of dopaminergic neurons by promoting synthesis of the free radical scavenger kynurenic acid (KYNA) and limiting the production of the free radical generator 3-hydroxykynurenine (3-HK). Finally, we show that expression of wild-type Scarlet is neuroprotective in a model of PD, suggesting that manipulating kynurenine metabolism may be a potential therapeutic option in treating PD.This article has an associated First Person interview with the first author of the paper.

Long-term potentiation results from spiking in one cell of an electrically coupled pair. Asymmetry of synapses increases following unidirectional activity. We suggest a calcium-based rule for electrical synapse plasticity. Abstract 2Activity-dependent changes of synapse strength have been extensively characterized at 3 chemical synapses, but the relationship between physiological forms of activity and strength at 4 electrical synapses remains poorly understood. For mammalian electrical synapses composed 5 of hexomers of connexin36, physiological forms of neuronal activity in coupled pairs has thus far 6 have only been linked to long-term depression; activity that results in strengthening of electrical 7 synapses has not yet been identified. The thalamic reticular nucleus (TRN), a central brain area 8 primarily connected by gap junctional (electrical) synapses, regulates cortical attention to the 9 sensory surround. Bidirectional plasticity of electrical synapses may be a key mechanism 10 underlying these processes in both healthy and diseased states. Here we show in electrically 11 coupled TRN pairs that tonic spiking in one neuron results in long-term potentiation of electrical 12 synapses between coupled pairs of TRN neurons. Potentiation is expressed asymmetrically, 13indicating that regulation of connectivity depends on the direction of use. Further, potentiation 14 depends on calcium flux, and we thus propose a calcium-based activity rule for bidirectional 15 plasticity of electrical synapse strength. Because electrical synapses dominate intra-TRN 16 connectivity, these synapses and their modifications are key regulators of thalamic attention 17 circuitry. More broadly, bidirectional modifications of electrical synapses are likely to be a 18 widespread and powerful principle for ongoing, dynamic reorganization of neuronal circuitry 19 across the brain. 20