Laboratory Research

The BC Epilepsy Society is committed to supporting laboratory research investigating the cause of epilepsy and for the discovery of new drugs to treat and one day find a cure for epilepsy. Since 2005, the BC Epilepsy Society has awarded grants totalling over $500,000 to support this important scientific research. This money is used to provide salary support for awardees and to purchase key laboratory equipment and supplies.


 

2014

Awardee: Dr. Stuart Cain

Proposal Title: Seizures and Sudden Unexpected Death in Epilepsy (SUDEP) in a Model of Generalized Epilepsy

Source of funds: BC Epilepsy Society

Competition: Research Award

Location: University of British Columbia

Award: $130,000

Resulting Publications:

The cellular mechanisms of neuronal swelling underlying cytotoxic edema https://www.ncbi.nlm.nih.gov/pubmed/25910210

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans https://www.ncbi.nlm.nih.gov/labs/articles/26490879

The T-type calcium channel antagonist Z944 rescues impairments in crossmodal and visual recognition memory in Genetic Absence Epilepsy Rats from Strasbourg https://www.ncbi.nlm.nih.gov/pubmed/27282256

Proposal Abstract:

Background and Rationale

Sudden unexpected death in epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in a patient with epilepsy, and affects approximately 1 in 1000 people with epilepsy every year.  The mechanisms underlying SUDEP are poorly understood, with few accurate models of the disorder available for research.  In our laboratory we study a strain of mice containing a single genetic mutation (S218L) in a type of calcium channel (called CaV2.1) that is widely expressed throughout the brain and controls neurotransmitter release at most synapses. The mutation is originally derived from patients with Familial Hemiplegic Migraine Type-1 (FHM-1), who in addition to migraine headaches also display absence and generalized seizures. Researchers have observed that greater than half of mice with two copies of the S218L FHM-1 mutation die unexpectedly. Post-mortem analyses have revealed no clear cause of death, with the only abnormal physiology found to be congestion/darkening of the vascular beds in the lungs. We hypothesize that the animals die as a result of either SUDEP or prolonged status epilepticus and propose investigating this model in order to determine the underlying cause of seizures and whether their occurrence correlates with sudden death. The results could both lead a new animal model for the study of SUDEP and provide informative insight into this novel, genetic-based severe generalized epilepsy model. Furthermore, we aim to utilize both a promising new clinical agent currently in clinical trials (Z944) and an existing antiepileptic drug (pregabalin) to determine whether reduction of generalized seizures both correlates with an extended lifespan of the animals and prevents sudden death. Together the studies will validate a novel convulsive seizure/SUDEP model and also provide a platform upon which to base future in vivo experiments aimed at defining epileptogenic mechanisms and testing new drugs. In support of our approach, we have previously utilized a multi-disciplinary strategy to successfully validate the genetic cause and neural mechanisms contributing to absence epilepsy in a well-known animal model (Genetic Absence Epilepsy Rats from Strasbourg). We further described the efficacy of a novel drug that specifically targets the underlying genetic cause of seizures and which is now undergoing clinical trials. 


 

2011

Awardee: Dr. Stuart Cain

Proposal Title: Pathophysiological contributions of T-type calcium channel variation towards thalamocortical network hyperexcitability and absence epilepsy

Source of funds: BC Epilepsy Society and Michael Smith Foundation for Health Research partnership

Competition: Trainee Award

Location: University of British Columbia

Award: $50,000 ($25,000 BC Epilepsy Society)

Resulting Publications:

Voltage-gated calcium channels and disease https://www.ncbi.nlm.nih.gov/pubmed/21698699

T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures https://www.ncbi.nlm.nih.gov/pubmed/22344687

Voltage-Gated Calcium Channels in Epilepsy https://www.ncbi.nlm.nih.gov/books/NBK98147/

T-type calcium channels in burst-firing, network synchrony, and epilepsy https://www.ncbi.nlm.nih.gov/pubmed/22885138

Low threshold T-type calcium channels as targets for novel epilepsy treatments https://www.ncbi.nlm.nih.gov/pubmed/23834404

Thalamocortical neurons display suppressed burst-firing due to an enhanced Ih current in a genetic model of absence epilepsy https://www.ncbi.nlm.nih.gov/pubmed/24953239

Proposal Abstract:

More than 50 million people worldwide suffer from epilepsy. Approximately 90 percent of those treated with current drugs experience significant side effects, and around 30 percent do not respond to current medical treatments at all. Therefore, significantly better treatments are required to improve the quality of life for epilepsy sufferers in Canada and worldwide. To achieve this, a far greater understanding of how the brain works both normally and during seizures is necessary.

Epilepsy is a difficult disorder to study in humans; however, in the 1980s, a strain of rats that naturally suffer from a type of seizure very similar to the human condition and involving the same brain regions was identified. These rats are extremely useful in helping us understand the causes of epilepsy in humans and test new drugs being developed to treat epilepsy. Two years ago, Dr. Stuart Cain’s research characterized a newly discovered genetic mutation in the epileptic rat strain responsible for a large portion of seizures. Epileptic seizures can be caused by changes in the way certain brain nerve cell proteins, known as "calcium channels," conduct electricity — the mutation characterized by Dr. Cain alters the way in which a specific type of calcium channel conducts electrical signaling. This was significant as these particular calcium channels are able to generate patterns of electrical pulses, known as “firing patterns,” predicted to contribute to epileptic seizures.

Dr. Cain’s research project aims to determine how the calcium channel mutation alters communication between nerve cells and affects different firing patterns. His laboratory is the only site in North America currently studying the epileptic rat strain. Understanding what causes the firing properties of epileptic nerves to change during seizures should allow the design of new drug treatments with the ability to block these changes directly, and to also reduce side effects compared to many of the broad-target drugs currently used clinically.


 

2008

Awardee: Dr. Jun Liu

Proposal Title: Role of Akt phosphorylation of GluR1 subunit of AMPA receptors in the receptor trafficking and synaptic plasticity

Source of funds: BC Epilepsy Society and Michael Smith Foundation for Health Research partnership

Competition: Trainee Award

Location: University of British Columbia

Award: $16,750

Resulting Publications:

Allosteric potentiation of glycine receptor chloride currents by glutamate http://www.nature.com/neuro/journal/v13/n10/full/nn.2633.html

Proposal Abstract:

Communication between neurons (brain cells) occurs at specialized junctions known as synapses. The process involves presynaptic neurons releasing neurotransmitter molecules, which then bind to membrane receptors on the surface of postsynaptic neurons – triggering the postsynaptic neuron to “fire.” The normal function of the brain depends on balancing the number of active receptors at the synaptic junction, so that neurons fire appropriately. Alzheimer’s disease and mental retardation show decreased receptor activity, whereas epilepsy and stroke show an excess of receptor activation. In effect, these conditions are marked by neural transmissions that are either too weak or too strong. Dr. Jun Liu previously practiced as a neurosurgeon in his native China. Now, he is studying how cellular and molecular mechanisms in brain cells support learning and memory. Recent findings indicate that the number of receptors activated on postsynaptic neurons can be rapidly regulated, suggesting a novel and efficient means by which the strength of synaptic transmission can be altered. Liu is investigating how such rapid changes in the number of postsynaptic receptors, and hence synaptic transmission strength, are initiated and carried out. Improved understanding of how receptor activity is regulated will help researchers learn how to correct receptor imbalances, offering new hope for a number of debilitating neurological conditions.


 

2007

Awardee: Dr. Kirk Mulatz

Proposal Title: Modulation of Cav3.2 T-type calcium channels through neuronal nitric oxide synthase activity

Source of funds: BC Epilepsy Society and Michael Smith Foundation for Health Research partnership

Competition: Trainee Award

Location: University of British Columbia

Award: $11,250

Resulting Publications:

Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies http://snutchlab.msl.ubc.ca/wp-content/uploads/2012/10/2009-Channels-3-2-Adams.pdf

Proposal Abstract:

Normal brain activity involves the controlled transmission of electrical impulses across networks of neurons (nerve cells). Occasionally, undesired electrical activity occurs within cellular networks and a response is necessary to suppress this outburst. Kirk Mulatz is investigating a negative feedback mechanism that allows neurons to inhibit this atypical electrical activity. He is focusing on the role of T-type calcium ion channels in generating this aberrant electrical activity, and exploring the effectiveness of inhibiting characteristics of the channels to inhibit the activity. Investigations into negative feedback mechanisms both increase understanding of normal brain activity and how cells respond to abnormal activity. A number of neuronal disorders such as epilepsies, mood disorders and chronic pain are associated with atypical brain activity, and the feedback mechanism that Mulatz is researching may contribute to restoring normal activity across cellular networks.


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