Loss of synaptic inhibition is a well-established cause of seizures, and this new study supports previous work from this laboratory showing that transplanted interneuronal precursors can become active participants in a hyperexcitable circuit and silence seizures in a genetic mouse model of epilepsy. Here, the model employed was a healthy mouse injected with a chemical convulsant, pilocarpine, that induces a hippocampal seizure focus sharing similarities with human temporal lobe epilepsy, but different in that brain development was otherwise normal and the circuit properties, while prone to generating seizures, are vastly different. In this model, grafted precursors not only reduced seizures, but also even improved performance deficits on behavioral tests relevant to hippocampal function. The authors conclude the approach holds promise not only for intractable epilepsies, but also perhaps other disorders that include altered hippocampal function such as Alzheimer’s disease and autism.

The groundbreaking aspects of this research are clear and mark a giant step toward a future...  Read more

Loss of synaptic inhibition is a well-established cause of seizures, and this new study supports previous work from this laboratory showing that transplanted interneuronal precursors can become active participants in a hyperexcitable circuit and silence seizures in a genetic mouse model of epilepsy. Here, the model employed was a healthy mouse injected with a chemical convulsant, pilocarpine, that induces a hippocampal seizure focus sharing similarities with human temporal lobe epilepsy, but different in that brain development was otherwise normal and the circuit properties, while prone to generating seizures, are vastly different. In this model, grafted precursors not only reduced seizures, but also even improved performance deficits on behavioral tests relevant to hippocampal function. The authors conclude the approach holds promise not only for intractable epilepsies, but also perhaps other disorders that include altered hippocampal function such as Alzheimer’s disease and autism.

The groundbreaking aspects of this research are clear and mark a giant step toward a future where severe focal epilepsies might be managed by cellular repair of damaged brain tissue rather than surgical removal. However, the findings are so counterintuitive that the authors should almost be chastened for their modest restraint in the Discussion. During brain development, over 21 different specific types of interneurons are painstakingly wired to precisely modulate the timing and firing patterns of hippocampal neurons. Who would imagine, given their diverse, highly individualized “personalities,” that simple addition of inexperienced newcomers could re-stabilize a normal pattern of synaptic inhibition in a network that is so severely compromised? And that their fates and excitability, which shift dramatically in immature brain, would retain properties similar to those they are intended to replace? The epileptic circuit in this model has been well studied and displays remarkable evidence of molecular and structural remodeling. Apparently, these fresh cells receive sufficient anatomic and biological guidance from the hyperactive network to quell the seizures, and the precise positioning of GABAergic synapses and the ratio of peptide co-transmitters they release are not as important as we may have thought.

While fresh interneurons may prove to be a panacea for lowering seizure thresholds, they may be less so for other measures of hippocampal function. An alternative view is that, whereas some behavioral measurements improved, this might be due to the reduction in seizures in these networks rather than the establishment of repaired hippocampal information processing. For the Alzheimer’s disease brain, the results are therefore less clear. So far, essentially all experimental mouse models of AD show seizure phenotypes, and recent data suggest that elimination of the seizures, for example, by tau removal, is accompanied by improved cognitive function. Some component of the cognitive loss may therefore actually represent an "epileptic pseudo-dementia" that may be reversible by silencing seizure activity. In the absence of seizures, it is unclear how well cellular grafting of interneurons, or any other type of cellular progenitor, will repair hippocampal function. Furthermore, the primarily neurodegenerative nature of the AD microenvironment suggests that even if temporarily effective, survival of the transplanted cells would be inexorably compromised, as they are in temporal lobe epilepsy, where cell death and hippocampal atrophy are also the hallmarks of the disease process. But if all we needed was a steady supply of fresh neurons, could an indwelling precursor brain cell reservoir supply them?

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