Catamenial-like Seizure Exacerbation in Mice with Targeted Ablation of Extrasynaptic Delta GABA-A Receptors in the Brain

Clossen BL, Reddy DS. Journal of Neuroscience Research 95(2017): 1906–1916

Purpose

• Catamenial epilepsy is a phenomenon where seizures in women worsen during certain periods in the menstrual cycle.
• In 2016, we presented a four-part article series summarizing catamenial epilepsy and what we know about it.
• Neurosteroids (or “steroids made in the brain”) can affect excitability of neurons.
  • They have a role in a variety of functions, such response to stress, memory, and depression.
  • Preliminary studies have shown that neurosteroids may play a role in catamenial epilepsy.
• Gamma amino butyric acid (GABA) is an inhibitory neurotransmitter responsible for dampening down excitability of neurons.
  • GABA acts by way of its receptors known as GABA receptors (GABARs); these receptors are made of proteins called “subunits.”
  • In neurons, these subunits come together in various combinations to form different GABAR subtypes.
  • One GABAR subtype containing the delta subunit is responsible for “tonic” (sustained) inhibition of neurons.
• In this study, the authors looked at the effect of delta subunit-containing GABARs on catamenial epilepsy.
• The “neurosteroid withdrawal method” is one way to simulate catamenial epilepsy in experimental animals.

Description of study

This study was done in female mice in the lab.

• The authors used two groups of mice – normal (wildtype = WT) mice, and those that had the delta subunit of the GABAR deleted (delta knockout mice = delta KO)
• All mice were subject to the neurosteroid withdrawal method of catamenial epilepsy that has been developed and used by other scientists previously.

Summary of study findings

• When mice were subject to the neurosteroid withdrawal method of catamenial epilepsy, delta KO mice had a starkly different response from WT mice.
• Delta KO mice had a higher susceptibility to seizures.
• Delta KO mice had more seizures that lasted a longer time compared to WT mice.
• When seizures did occur, they were more intense in delta KO than in WT mice.

What does this mean?

• This article highlights the role of the delta subunit of GABAR subunit in catamenial epilepsy.
• Since removal of the delta subunit of GABARs rendered mice more susceptible to seizures, the authors suggest that delta subunit containing GABARs may have a protective role in catamenial epilepsy.
• Catamenial epilepsy is a complex phenomenon without effective treatment options.
• The data gleaned in this study can be used to develop targeted therapies for catamenial seizures in the future.

Article published in Journal of Neuroscience Research, February 2017.