Project Summary/Abstract
Epilepsy is a common neurological disorder that affects approximately 70 mln people. For many patients,
epilepsy can be controlled through pharmaceutical therapies; however, approximately 30% of patients develop
refractory epilepsy that cannot be controlled with current pharmaceutical interventions. Refractory epilepsy is
associated with a high risk for sudden unexpected death in epilepsy (SUDEP), which is the leading cause of
death in this patient population. In addition, uncontrolled epilepsy and frequent seizures are associated with
progressive cognitive decline, as well as significant behavioral and psychiatric comorbidities. Thus, it is of
paramount importance to identify novel critical therapeutic targets for patients with refractory epilepsy. The main
objective of this proposal is to establish the role of the mitochondrial Ca2+ uniporter (MCU) in regulating synaptic
function, neural network activity and seizure susceptibility. MCU is the core component of the mitochondrial Ca2+
uptake complex and is involved in the regulation of Ca2+ signaling, bioenergetics and cell death. Our focus on
MCU is inspired by several novel observations we made during our pilot studies. First, we found that MCU
knockout (KO) produces robust anticonvulsant effects both in vivo and in vitro. Second, deleting MCU specifically
in GABAergic, but not in glutamatergic, neurons was sufficient to produce an anticonvulsant effect. Third, MCU
deletion enhanced GABAergic synaptic transmission, but did not alter glutamatergic transmission or intrinsic
neuronal excitability. Fourth, MCU deletion protected neurons from glutamate-induced Ca2+ deregulation and
toxicity. The latter is important because excitotoxicity contributes significantly to neuronal damage in epilepsy.
Collectively, these data suggest that inhibiting MCU would provide a dual benefit in the context of epilepsy, first
by increasing seizure threshold, and second, by protecting neurons from excitotoxicity associated with seizures.
We hypothesize that MCU plays an important role in regulating GABAergic synaptic transmission and neural
activity, and that MCU deletion produces anticonvulsant effects by enhancing GABAergic synaptic transmission
and preventing neural network hyperexcitability. We also hypothesize that MCU deletion provides protection
from neurotoxicity associated with seizures. These central hypotheses will be tested in 3 specific aims. Aim 1
will establish the roles of GABAergic and glutamatergic neurons in the anticonvulsant effect of MCU deletion.
Aim 2 will determine the role of MCU at inhibitory and excitatory central synapses. Aim 3 will determine the role
of MCU in epilepsy-induced neuronal toxicity. The proposed studies will provide mechanistic insight into a
previously unrecognized role of mitochondrial Ca2+ transport in regulating the activities of synaptic networks and
susceptibility to hyperexcitability and seizures, and could lead to development of new strategies targeting
mitochondrial Ca2+ transport and MCU for the treatment of epilepsy as well as other neurological disorders
associated with aberrant neural activity.
