Two major classes of inhibitory neurons are dysfunctional in Dravet syndrome mice

Rajalaxmi Natarajan, PhD
Thu, 04/09/2015

Dravet syndrome is a rare and catastrophic form of incurable epilepsy that begins in infancy. Initially, these children develop normally but by the second year of life, they exhibit a progressive decline. It starts initially as febrile seizures i.e. seizures triggered by high fever but eventually progresses to severe spontaneous seizures. Over time, these children commonly exhibit developmental delays in cognitive and sensory abilities, and autistic traits. Moreover, the incidence of SUDEP (sudden unexplained death in epilepsy) is high among these patients.

More than 80% of Dravet cases are caused by a mutation in SCN1A gene that codes for a voltage-gated sodium channel protein.  All cells have two major structural components; the first is the cell membrane, a very thin oily barrier that separates the second component, the cytoplasm, from the surrounding environment. Cells use channel proteins to form “tunnels” in the membrane to shuttle specific ions (e.g.: sodium) to and fro.  In excitable cells such as neurons, electrical activity serves as a trigger to open channels (i.e to voltage-gate them) and let ions quickly move across the membrane and generate new electrical activity.

All neurons communicate with each other via these electrical signals.  There are many types of nerve cells in the brain.  However, in the neocortex there are two major subclasses; principle neurons and interneurons.  Principle neurons are also called pyramidal cells and excite other cells while interneurons are inhibitory and dampen the electrical activity of pyramidal cells. 

In terms of Dravet syndrome, a few years ago researchers reported that removal of SCN1A voltage-gated sodium channels from inhibitory interneurons (but not pyramidal cells) caused Dravet-like symptoms in mice. This suggested that the seizure activity in Dravet patients may be attributable to overall hyperactivity of cortical networks due to insufficient inhibition from inhibitory interneurons. Since then, a lot of research in Dravet mouse models has focused on the contribution of one major subtype on inhibitory interneurons – cells that contain the protein Parvalbumin.  Whether other interneuron subtypes were involved in this disease had never been explored.

In a recent study published in the Proceedings of the National Society (PNAS) USA, Tai et al1., implicated Martinotti cells, the somatostatin-expressing subtype of interneurons found in the cerebral cortex, in Dravet syndrome.

Parvalbumin interneurons and Martinotti cells together form about 80% if the inhibitory interneurons in the cortex, and can be differentiated based on the marker proteins they express and the targets they project to.
In this study, the authors recorded neuronal activity in these two classes of interneurons from brain slices taken from mice deficient in Scn1a. They chose to record 20-22 days after birth, when the pups are vulnerable to many spontaneous seizures and are at the highest risk for SUDEP (sudden unexpected death).

In keeping with results from previous studies, they found that parvalbumin interneurons were unable to inhibit pyramidal cells normally and were intrinsically less excitable. Interestingly, they also found that Martinotti cells, also fired fewer action potentials. This means that they are less capable of dampening the activity of nearby neurons, which could result in overall excitation in the entire circuit. Thus they could clearly contribute to frequent seizures observed in Dravet patients.

While these results remain to be extended to humans, this study suggests that in addition to parvalbumin interneurons, Martinotti cells could be the potential new cellular target for therapy development for this devastating childhood epilepsy.

Reference:

1. Tai et al., Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A. 2014 Jul 29; 111(30): E3139-48. doi: 10.1073/pnas.1411131111.

Learn More about Dravet syndrome
Dravet syndrome Foundation