Reduction in focal ictal activity following transplantation of MGE interneurons requires expression of the GABAA receptor α4 subunit

Abstract

Despite numerous advances, treatment-resistant seizures remain an important problem. Loss of neuronal inhibition is present in a variety of epilepsy models and is suggested as a mechanism for increased excitability, leading to the proposal that grafting inhibitory interneurons into seizure foci might relieve refractory seizures. Indeed, transplanted medial ganglionic eminence interneuron progenitors (MGE-IPs) mature into GABAergic interneurons that increase GABA release onto cortical pyramidal neurons, and this inhibition is associated with reduced seizure activity. An obvious conclusion is that inhibitory coupling between the new interneurons and pyramidal cells underlies this effect. We hypothesized that the primary mechanism for the seizure-limiting effects following MGE-IP transplantation is the tonic conductance that results from activation of extrasynaptic GABAA receptors (GABAA-Rs) expressed on cortical pyramidal cells. Using in vitro and in vivo recording techniques, we demonstrate that GABAA-R α4 subunit deletion abolishes tonic currents (Itonic) in cortical pyramidal cells and leads to a failure of MGE-IP transplantation to attenuate cortical seizure propagation. These observations should influence how the field proceeds with respect to the further development of therapeutic neuronal transplants (and possibly pharmacological treatments).

Restrained Dendritic Growth of Adult-Born Granule Cells Innervated by Transplanted Fetal GABAergic Interneurons in Mice with Temporal Lobe Epilepsy

“…Some evidence suggests that MGE transplants also reduce mossy fiber sprouting (Henderson et al, 2014; but see Hunt et al, 2013). After transplantation into the hippocampus of mice with TLE, fetal mouse MGE progenitors were linked to increased spontaneous IPSCs in hippocampal GCs (Henderson et al, 2014) and increased phasic and tonic inhibition in other populations of host brain neurons (Baraban et al, 2009; Hsieh and Baraban, 2017) via α4 subunit containing GABA A receptors (Jaiswal et al, 2015). The notion that transplanted neurons integrate into host brain circuits and provide synaptic inhibition is further supported by optogenetic experiments showing that stimulation of transplanted channelrhodopsin 2 (ChR2)-expressing GABAergic neurons induced strong IPSCs in hippocampal neurons (Henderson et al, 2014; Hsieh and Baraban, 2017).…”

Transplantation of GABAergic interneurons for cell-based therapy

“…MGE grafts enhance both synaptic and extrasynaptic inhibition (Baraban et al, 2009). Interestingly, the requirement of extrasynaptic GABA-A receptors for the transplant-mediated dampening of seizure propagation in the 4-AP model was recently shown (Jaiswal et al, 2015). Given the heterogeneity of MGE transplant-derived interneurons, it will be important to identify whether specific subtypes may prove therapeutic for specific forms of seizures.…”

Contemplating stem cell therapy for epilepsy-induced neuropsychiatric symptoms

“… 9 It is suggested that there is a connection between the pyramidal neurons and the newly formed interneurons which produces the inhibitory effect. 87 Further investigation in clinical GABAergic cell therapy must explore the long-term effects of grafting, results in drug-resistant epilepsy, and usefulness in reducing the cognitive and mood impairments associated with epilepsy. 9 …”