Hunt RF, Girskis KM, Rubenstein JL, Alvarez-Buylla A, Baraban SC.
GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior.
Nat Neurosci. 2013 Jun;16(6):692-7.
PubMed.
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?
This is an interesting article, but the benefits of replacing inhibitory neurons with stem cells in Alzheimer’s disease (AD) are not completely clear to me. Alterations of GABAergic neurons have been related to a variety of diseases, but in the cerebral cortex (neocortex and hippocampus), the vast majority of degenerating neurons in AD are pyramidal (glutamatergic) neurons. Since the dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses, and they are fundamental structures in memory, learning, and cognition, the disappearance of dendritic spines constitutes what is believed to be one of the most important early events in the pathogenesis of AD.
Nevertheless, it is true that there may be a relationship between alterations of cortical circuits in Alzheimer’s disease and epilepsy or epileptiform brain activity. For example, we have observed that the membrane surfaces of pyramidal neurons in contact with plaques (in both humans and animal models) lack GABAergic perisomatic synapses, and that a large proportion of plaques are in contact with neurons (see DeFelipe comment). In experimental animals, small reductions in the efficacy of GABA-mediated inhibition can lead to synchronized epileptiform activity; hence, a loss of perisomatic GABA axon terminals may overexcite neurons in contact with plaques.
The progressive appearance of plaques throughout the cerebral cortex would steadily increase the susceptibility of developing and propagating seizures by increasing the numbers of hyperactive neurons nearby. Thus, it is hard to see how stem cell replacement therapy may help to repair these widely spread changes in GABAergic circuits, and most importantly, what (if any) its relationship could be to the protection of pyramidal neurons, the most susceptible neurons in the cerebral cortex to damage in AD.
Garcia-Marin V, Blazquez-Llorca L, Rodriguez JR, Boluda S, Muntane G, Ferrer I, Defelipe J.
Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques.
Front Neuroanat. 2009;3:28.
PubMed.
León-Espinosa G, Defelipe J, Muñoz A.
Effects of amyloid-β plaque proximity on the axon initial segment of pyramidal cells.
J Alzheimers Dis. 2012;29(4):841-52.
PubMed.
Comments
Baylor College of Medicine
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.
View all comments by Jeffrey L. NoebelsFor 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?
Instituto Cajal (CSIC)
This is an interesting article, but the benefits of replacing inhibitory neurons with stem cells in Alzheimer’s disease (AD) are not completely clear to me. Alterations of GABAergic neurons have been related to a variety of diseases, but in the cerebral cortex (neocortex and hippocampus), the vast majority of degenerating neurons in AD are pyramidal (glutamatergic) neurons. Since the dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses, and they are fundamental structures in memory, learning, and cognition, the disappearance of dendritic spines constitutes what is believed to be one of the most important early events in the pathogenesis of AD.
Nevertheless, it is true that there may be a relationship between alterations of cortical circuits in Alzheimer’s disease and epilepsy or epileptiform brain activity. For example, we have observed that the membrane surfaces of pyramidal neurons in contact with plaques (in both humans and animal models) lack GABAergic perisomatic synapses, and that a large proportion of plaques are in contact with neurons (see DeFelipe comment). In experimental animals, small reductions in the efficacy of GABA-mediated inhibition can lead to synchronized epileptiform activity; hence, a loss of perisomatic GABA axon terminals may overexcite neurons in contact with plaques.
The progressive appearance of plaques throughout the cerebral cortex would steadily increase the susceptibility of developing and propagating seizures by increasing the numbers of hyperactive neurons nearby. Thus, it is hard to see how stem cell replacement therapy may help to repair these widely spread changes in GABAergic circuits, and most importantly, what (if any) its relationship could be to the protection of pyramidal neurons, the most susceptible neurons in the cerebral cortex to damage in AD.
See also:
Comment by DeFelipe J. on Chicago: AD and Epilepsy—Joined at the Synapse? 9 Dec 2009.
References:
Garcia-Marin V, Blazquez-Llorca L, Rodriguez JR, Boluda S, Muntane G, Ferrer I, Defelipe J. Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques. Front Neuroanat. 2009;3:28. PubMed.
León-Espinosa G, Defelipe J, Muñoz A. Effects of amyloid-β plaque proximity on the axon initial segment of pyramidal cells. J Alzheimers Dis. 2012;29(4):841-52. PubMed.
View all comments by Javier DeFelipeMake a Comment
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