Physiology

Describing at Cellular Level

Epilepsy is one of the most common neurological brain disorders characterized by repeated seizures: a sudden change in the electrical functioning of the brain. It is in which the balance between cerebral excitability and inhibition is disrupted towards uncontrolled excitability. There are controls in the body that keep the neurons from discharging excessive action potentials. Disrupting the medium that is responsible for the action potential firing can lead to seizures. There are definite differences between immature and mature brains in the pathophysiology and the consequences and reasons for recurrent seizures. As originally described by J. Hughlinds Jackson in 1870, a seizure is an “excessive discharge of the nerve tissue on a muscle”[13]. At the lowest level, the nervous system is the function of an ionic environment: the chemical and electrical gradients create surroundings for electrical activity. The control of resting membrane potential becomes crucial to prevent excessive discharging of action potentials. Normally, there is a high concentration of potassium inside the neuron and there is a high extracellular concentration of sodium outside the neuron. If this balance is tampered with, then this leads to depolarization which could further lead to action potential release. Both the location of the initial event and the propagation pattern of the discharge of the action potential will determine the behavioral changes that occur during the seizures. Changes in the sodium channel result in a decrease in the threshold for the action potential. It is also proven that mutations in the voltage-dependent sodium channels lead to epilepsy. The mutation does not block the sodium channels but rather changes the function within the channels. The modulation in the sodium channels could influence the neurological function inside the Central Nervous System.

Along with the excessive action potential discharging, the synchronization of neurons also plays a major role in causing repetitive seizures. To understand how neurons synchronize, scientists Matsumoto and Marsan found that “the electrographic events recorded at the cortical surface during seizures corresponded to paroxysmal depolarization shifts (PDS) of cortical pyramidal cells occurring synchronously”[12]. The synchronization of discharges of the neurons is called the Paraxomal Depolarization Shift (PDS). During the PDS, the cell membrane experiences high voltage(15mV) and long durations of depolarization(200ms). The pyramidal cells of the cortex are interconnected by glutamate synapses. Gap junctions on the cortical neurons are another way to synchronize neurons. They allow a low-resistance pathway for the current flow between two different cells, so this results in rapid synchronization of neurons. Along with gap functions, inhibition is one of the reasons for the synchronization of neurons. Gaba Aminobutric acid, GABA, controls somatic inhibition and makes numerous connections to the pyramidal cells in a local area. Therefore, a discharge of a single interneuron can synchronously hyperpolarize a population of pyramidal cells. As the GAGA inhibition decreases, the voltage-dependent currents of the pyramidal cells become activated. These currents are relatively inactive during the resting potential[12]. In epilepsy, the individual experiences recurrent seizures, this could be due to the reasons and changes arising from the inside of their body as well. The changes include the growth of axon collaterals of the excitatory neurons and the use of glutamate as a neurotransmitter that is called principal cells. When researching epilepsy and its effect on the animal brain, researchers were able to prove that in patients with temporal lobe epilepsy, the axons of the granule cells develop new collaterals and new collaterals extend for some distance. They don’t terminate in the normal location, but rather in novel lamina which contains large amounts of granule cell dendrites.

Citation: https://www.nature.com/articles/pr200150/figures/3.

Caption: The image shows the depolarization and hyper-polarization of the action potentials within the cell.

Although seizures can change multiple areas within the brain, the hippocampus is proven to be the most vulnerable and affected by seizure-induced injury. Hippocampus, the brain structure within the temporal lobe, plays a major role in learning and memory. The seizure-induced injury causes neural loss in the hippocampal fields within the region: CA1, CA3, dentate granule cell layer, and dentate hilus[12]. Cellular damage occurs due to the excessive excitatory neurotransmitter release during which the NMDA receptors and voltage-gated calcium channels get activated allowing the Ca2+ to enter the cell. High calcium concentrations inside the cell lead to the generation of reactive oxygen species thru the activation of nitric oxide synthase, oxidative phosphorylation in the mitochondria, and activate a large range of enzymes such as lipases that have unfavorable consequences for the functions within the cell which could affect the entire system within the brain of the human body with epilepsy.

Seizures in the human brain lead to vast forms of synaptic plasticity which includes long-term potentiation of the synaptic responses. Following, there are alterations in the cortical network in the neurons that result in the deduction of the thresholds of the seizure. Seizures have proven to activate hundreds of genes that lead to axonal growth. Thus, recurrent and prolonged seizures can cause synaptic reorganization with aberrant growth of granule cell axons in the supragranular zone of the fascia dentata and region of CA3(region within hippocampus). Blocking one of the glutamate sub-receptors (NMDA) is also an indication of the excitation within the synaptic plasticity. NMDA also results in the development of mossy fiber development. The formations, namely sprouting and new synapse, occur mostly in the other brain regions(CA1 pyramidal neurons) where it is proven that newly formed synapses produce an enhanced frequency of synaptic currents. These modulations within the cell appear to be a general response to the hyperactivity by the cortical networks of the neurons paving for the seizures to be recurrent and lasting.