The Goldin lab investigates the role of voltage-gated sodium channels in normal and abnormal physiology of the central nervous system. There are two aspects to these studies. The first is to examine the effects of abnormal sodium channel function on the animal, and the second is to determine the mechanisms by which sodium channels traffic to different regions of the neuron.

The Goldin lab investigates the role of voltage-gated sodium channels in normal and abnormal physiology of the central nervous system. There are two aspects to these studies. The first is to examine the effects of abnormal sodium channel function on the animal, and the second is to determine the mechanisms by which sodium channels traffic to different regions of the neuron.

The studies to determine how sodium channel mutations cause CNS disease use three approaches. First, the lab is studying the effects of spontaneous mutations in mice. An example is the jolting mouse, which results from a single amino acid change in a sodium channel expressed in the cerebellum, causing ataxia and involuntary movements. The second approach is to construct transgenic mice expressing sodium channels with well-defined mutations. They have expressed a channel with incomplete inactivation in the CNS of mice, which resulted in epilepsy that was manifested as hippocampal seizures and early mortality. The final approach is to examine the effects of epilepsy causing mutations in genes encoding human CNS sodium channels. An example is Generalized Epilepsy with Febrile Seizures Plus type 2, which is caused by mutations in sodium channel subunits. The results from these studies should help to understand how alterations in sodium channel function alter neuronal activity in the CNS.

With respect to trafficking, the lab is examining how different sodium channels localize in different regions of CNS neurons. There are multiple sodium channel isoforms, including at least four that are expressed in the CNS. These subtypes are present in different intracellular locations, which is likely to be significant in both normal and pathological function. For example, one specific isoform is uniquely involved in the propagation of electrical impulses in myelinated axons. The approach is to construct channels either linked to different color variants of GFP or linked to different synthetic epitopes, after which the channels are expressed in tissue culture cell lines and in primary neurons to examine intracellular localization. They are also constructing chimeric channels to identify the portions of the molecule that are important for the localization differences. These studies should help to define the molecular mechanisms by which different sodium channel isoforms are localized in specific regions of CNS neurons.

The studies to determine how sodium channel mutations cause CNS disease use three approaches. First, the lab is studying the effects of spontaneous mutations in mice. An example is the jolting mouse, which results from a single amino acid change in a sodium channel expressed in the cerebellum, causing ataxia and involuntary movements. The second approach is to construct transgenic mice expressing sodium channels with well-defined mutations. They have expressed a channel with incomplete inactivation in the CNS of mice, which resulted in epilepsy that was manifested as hippocampal seizures and early mortality. The final approach is to examine the effects of epilepsy causing mutations in genes encoding human CNS sodium channels. An example is Generalized Epilepsy with Febrile Seizures Plus type 2, which is caused by mutations in sodium channel subunits. The results from these studies should help to understand how alterations in sodium channel function alter neuronal activity in the CNS.

With respect to trafficking, the lab is examining how different sodium channels localize in different regions of CNS neurons. There are multiple sodium channel isoforms, including at least four that are expressed in the CNS. These subtypes are present in different intracellular locations, which is likely to be significant in both normal and pathological function. For example, one specific isoform is uniquely involved in the propagation of electrical impulses in myelinated axons. The approach is to construct channels either linked to different color variants of GFP or linked to different synthetic epitopes, after which the channels are expressed in tissue culture cell lines and in primary neurons to examine intracellular localization. They are also constructing chimeric channels to identify the portions of the molecule that are important for the localization differences. These studies should help to define the molecular mechanisms by which different sodium channel isoforms are localized in specific regions of CNS neurons.