Recurring seizures Disrupt the Fine Balance of Synaptic Homeostasis

Rajalaxmi Natarajan, PhD
Thu, 11/13/2014

Excessive and synchronized nerve cell activity has long known to underlie the generation of seizures. A review published in the July 2014 issue of Advances in Experimental Medicine and Biology, proposes a novel hypothesis. It suggests that compensatory mechanisms engaged by the synapses in an epileptic brain to control run-away neuronal hyper-excitation end up having other detrimental and long-term consequences on the functioning of nerve cells, thereby impacting learning and memory.

Synapses are highly specialized junctions that facilitate rapid and precise transmission of signals between nerve cells. They are essential for various motor and cognitive processes such as learning, memory or decision-making.  Interestingly, neuronal synapses are not static structures, but are highly dynamic. This means they can strengthen or weaken over time depending on the level and type of activity they experience. This unique feature allows synapses to quickly and efficiently adapt to changes in the strength and frequency of specific inputs.

Many excitatory synapses elicit rapid and continuous positive feedback responses, a phenomenon termed “Hebbian plasticity.” Synapses encountering excitatory signals can be potentiated for long periods of time – from a few hours to several days. This type of plasticity is called long-term potentiation or LTP and is thought by most neuroscientists to be the cellular basis for many forms of learning as well as formation and retrieval of memories.

A major drawback of having such a self-perpetuating mechanism of plasticity is that it is highly prone to destabilization. Persistent Hebbian plasticity can lead to synaptic run away hyper-excitation, which could easily result in pathological conditions. In fact, it is well known that seizures are a result of excessive hyper-excitation of neurons leading to sudden, involuntary contractions of muscles.

Epilepsy is the chronic condition in which patients suffer seizures of varying frequency and severity. While many of them have a genetic basis, there are other causes of epileptic seizures: traumatic brain injury, stroke, neurodegenerative diseases, brain tumors and infections of the central nervous system.

In cases of acquired epilepsy, it has been observed that there is often a “silent” period between the precipitating event and the appearance of the first seizure. During this apparent latency, many gradual molecular, cellular and circuit level changes occur that lead to a re-modeling of brain networks. The formation of additional excitatory synapses is thought to be one mechanisms leading to increased network excitability and frequent seizures. Since the brain operates as a positive feedback system, the event’s effects would exacerbate over time.

Based on animal studies conducted in the last decade, it has become increasingly apparent that when faced with drastic imbalances in brain network activity, synapses have strategies to retain a state of physiological equilibrium or “homeostasis.” These compensatory mechanisms act like a typical thermostat. They sense disturbances in the network activity, identify the magnitude to which it has been altered from the physiological set point and deploy compensatory responses, including, for example, pruning excess synapses, to reset activity back to normal levels. Thus, typically, synaptic homeostatic mechanisms are thought to stabilize nerve cell activity and counterbalance excessive Hebbian plasticity.

While it still remains to be firmly established that altered synaptic homeostatic response plays an important role in epilepsy, mounting evidence suggests that compensatory mechanisms such as decreased dendritic branching and reduction in excitatory synapse number are induced during seizures to counter the hyper-excitation.

In the short-term, these may help to restore the synaptic imbalance and alleviate the seizure symptoms. Also, these may partly explain why certain types of childhood epilepsies spontaneously resolve, especially as the children grow up and synaptic homeostatic mechanisms gradually get established.

It appears, however, that in cases of severe or intractable cases of epilepsy, persistent deployment of compensatory strategies may result in harmful consequences. For instance, long-term dendritic growth suppression and/or reduction in the number of excitatory synapses could eventually impair learning and memory. Thus, overuse of synaptic homeostatic mechanisms could ultimately compromise Hebbian forms of plasticity and contribute to learning and memory deficits that often accompany severe forms of epilepsy.

The hypothesis proposed in this review eloquently describes the conundrum of identifying successful therapeutic strategies for chronic intractable epilepsies. While the use of compensatory strategies may be helpful in the short-term in controlling seizures, upsetting the delicate balance between Hebbian and homeostatic synaptic plasticity could eventually lead to additional detrimental effects of nerve cells and the operations of neural network.


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