Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

Abstract

Interneuron progenitors from the embryonic medial ganglionic eminence (MGE) can migrate, differentiate, and enhance local inhibition after transplantation into the postnatal cortex. Whether grafted MGE cells can reduce ictal activity in adult neocortex is unknown. We transplanted live MGE or killed cells (control) from pan green fluorescent protein expressing mice into adult mouse sensorimotor cortex. One week, 2 and 1/2 weeks, or 6 to 8 weeks after transplant, acute focal ictal epileptiform discharges were induced by injection of 4-aminopyridine (4-AP) 2 mm away from the site of transplantation. The local field potential of the events was recorded with 2 electrodes, 1 located in the 4-AP focus and the other 1 in the transplantation site. In all control groups and in the 1-week live cell transplant, 4-AP ictal discharges revealed no attenuation in power and duration from the onset site to the site of transplantation. However, 2.5 or 6~8 weeks after MGE transplants, there was a dramatic decrease in local field potential power at the MGE transplanted site with little decrease in ictal duration. Surprisingly, there was no relationship between grafted cell distribution or density and the degree of attenuation. As remarkably low graft densities still significantly reduced discharge power, these data provide further support for the therapeutic potential of interneuron precursor transplants in the treatment of neocortical epilepsy.

Transplantation of GABAergic interneurons for cell-based therapy

“…2). Accordingly, transplant-derived cells have been shown to migrate distances up to 2.5 mm in the adult rodent brain (Davis et al, 2015; De la Cruz et al, 2011; Hunt et al, 2013; Martínez-Cerdeño et al, 2010) and 5 mm in the neonate (Alvarez-Dolado et al, 2006; Southwell et al, 2010). Second, in line with the postnatal maturation of inter-neurons in vivo (Okaty et al, 2009), following their migratory phase, transplanted MGE interneurons develop over the course of several weeks in the heterochronic environment before acquiring mature morphology, marker expression, and electro-physiological properties (Alvarez-Dolado et al, 2006; Howard and Baraban, 2016; Southwell et al, 2010) (Fig.…”

“…Accordingly, animal survival rate was also increased among transplant recipients compared to controls. Interneuron transplantation in the adult cortex also reduces seizure propagation as indicated by local field potential measurement upon focal administration of 4-aminopyridine (4-AP), a potent convulsant and potassium channel blocker (De la Cruz et al, 2011). Here, the beneficial impact of MGE grafts on epileptiform activity was detected as early as 2.5 weeks posttransplant and was also found to be independent of the extent of transplanted cell survival, which suggests that a critical amount of grafted cells is required for optimal tuning of neuronal inhibition (Southwell et al, 2010; Tang et al, 2014).…”

“…Inconsistencies in the timing of MGE graft efficacy suggest that those mechanisms may not be conserved across seizure models. For instance, while the kinetics of seizure suppression observed in the pilocarpine model strongly suggest a role for synaptic mechanisms (Henderson et al, 2014; Hunt et al, 2013), the early effects observed in the 4-AP model (De la Cruz et al, 2011) would indicate a possible role for nonsynaptic mechanisms. MGE grafts enhance both synaptic and extrasynaptic inhibition (Baraban et al, 2009).…”

Homochronic Transplantation of Interneuron Precursors into Early Postnatal Mouse Brains

“…Numerous studies have transplanted embryonic MGE cells directly into a variety of brain regions, with the consensus results that grafted cells mature and release GABA to generally inhibit the local endogenous circuitry 14, 15, 16, 17, 18, 19 . These promising observations have generated significant interest in using human induced pluripotent stem cell (hIPSC)-derived interneurons to treat a variety of brain diseases.…”

Optogenetic tools for modulating and probing the epileptic network

“…Embryonic MGE cell transplants have been shown to have anti-epileptogenesis properties (Baraban et al, 2009; De la Cruz et al, 2011). Henderson et al used optogenetic activation of transplanted MGE cells expressing ChR2 to demonstrate robust hyperpolarizations in granule cells (Henderson et al, 2014).…”