Epileptogenesis Structural Alterations Leading To Epilepsy

One of the great mysteries in neuroscience is how the brain becomes permanently altered to create the substrate for chronic epilepsy. Sometimes an etiology or structural cause can be determined, but often no explanation is found. One type of epilepsy, temporal lobe epilepsy or TLE, can be a consequence of structural alterations to the hippocampus, one of the most epilepsy-prone (epileptogenic) areas of the brain. Hippocampal injury, such as caused by status epilepticus (arbitrarily defined as a seizure lasting more than 30 min), may produce persistent hyperexcitability long after the end of a prolonged seizure. This chronic hyperexcitability is a result of the combined effects of several structural alterations: neuronal death, gliosis or mesial temporal sclerosis, and the growth of new, abnormal axonal connections ("sprouting"). Figure 7 depicts how such sprouting might work by producing aberrant excitatory connections. Dentate granule neurons (Fig. 7A, circles 1, 2) receive all incoming activity entering the hippocampus. Ordinarily, dentate neurons fire only single action potentials (right panel,

Fig. 7. Simplified depiction of sprouting in the hippocampal dentate gyrus. (A) Normal situation: left, Dentate granule neurons (1, 2) make excitatory synapses (E) onto dendrites of hippocampal pyramidal neurons (3, 4); right, activation of dentate neuron 2 causes single action potential in pyramidal neuron 3, after a synaptic delay. (B) As a consequence of status epilepticus, many pyramidal neurons die (4, dashed outline), leaving axons of dentate neuron 1 without a postsynaptic target; those axons then "sprout" and innervate the dendrites of other granule neurons (thick curved arrow), creating the substrate for a hyperexcitable circuit. Now, when neuron 1 is activated, multiple action potentials are fired in neuron 2, and therefore in neuron 3 (right traces). As described in the text, this diagram is simplified and, in fact, neurons of numerous types in the dentate hilus (labeled H) are also involved in the outcome of seizure-induced synaptic plasticity. The resultant circuit function will depend on the character (excitatory or inhibitory) and connectivity of these interneurons. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

Fig. 7. Simplified depiction of sprouting in the hippocampal dentate gyrus. (A) Normal situation: left, Dentate granule neurons (1, 2) make excitatory synapses (E) onto dendrites of hippocampal pyramidal neurons (3, 4); right, activation of dentate neuron 2 causes single action potential in pyramidal neuron 3, after a synaptic delay. (B) As a consequence of status epilepticus, many pyramidal neurons die (4, dashed outline), leaving axons of dentate neuron 1 without a postsynaptic target; those axons then "sprout" and innervate the dendrites of other granule neurons (thick curved arrow), creating the substrate for a hyperexcitable circuit. Now, when neuron 1 is activated, multiple action potentials are fired in neuron 2, and therefore in neuron 3 (right traces). As described in the text, this diagram is simplified and, in fact, neurons of numerous types in the dentate hilus (labeled H) are also involved in the outcome of seizure-induced synaptic plasticity. The resultant circuit function will depend on the character (excitatory or inhibitory) and connectivity of these interneurons. (Modified with permission of the American Academy of Pediatrics from ref. 58.)

trace 2). Dentate neurons innervate hippocampal pyramidal neurons (triangles: 3, 4), which fire single action potentials in response to dentate input (right panel, trace 3). Status epilepticus typically causes death of pyramidal cells (owing to overactivation of NMDA receptors and excessive Ca2+ entry, as discussed in Section 4.2.) but spares dentate neurons (Fig. 7B). Therefore, axons of dentate neuron 1 are left without a postsy-naptic target, so they turn around and wind their way back to innervate their own dendrites and those of neighboring dentate neurons, forming "autoexcitatory," reverberating excitatory circuits (Fig. 7B, left). Now, dentate neuron 2 receives excessive excitatory input and fires multiple action potentials, causing surviving pyramidal neurons to do the same (trace 3). Rather than being unique to hippocampus, sprouting may comprise a more general mechanism by which brain circuits become hyperexcitable.

However, the circuit diagram in Fig. 7 is oversimplified. In fact, interspersed between the dentate granule cells and the pyramidal neurons (in the dentate "hilus," labeled H) are many other types of neuron and interneuron, some excitatory, others inhibitory. Depending on which of hilar neurons are silenced (by seizure-induced cell death) or activated by seizure activity, the physiology of the circuit could be vastly altered (39). This synaptic flexibility is an example of seizure-induced plasticity and can give rise to complicated circuits that can either compensate for or exacerbate the initial seizure situation.

To make matters even more complicated, seizures can induce neurogenesis in certain areas of the brain, that is, the birth of new neurons (even in the adult brain). This phenomenon is especially prominent in the dentate gyrus. Again, it can give rise to increased or decreased excitability depending on the connectivity and type of newly born neurons. The role of neurogenesis in epileptogenesis is being investigated (40).

In addition to injury-induced alterations of structural neuronal networks, neural circuits can also be naturally epileptic. Children with abnormal brain development (dysge-nesis) have a high predisposition to epilepsy. Aided by advances in neuroimaging, especially MRI, an ever-increasing number of dysgenetic cortical lesions is being delineated. Some of these lesions are quite subtle yet are sufficient to comprise an epileptic circuit (41). Disruption at any step in the complex sequence of brain development, e.g., neuronal proliferation, migration, synaptogenesis, can lead to abnormal circuit function and epilepsy. Examination of dysgenetic cortical tissue from animals with experimentally induced abnormal brain development reveals widespread evidence of hyperex-citable circuitry (42).

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