The Dentate Gyrus and Temporal Lobe Epilepsy: An "Exciting" Era

Abstract

This review describes developments in epilepsy research during the last 3 to 4 decades that focused on the dentate gyrus (DG) and its role in temporal lobe epilepsy (TLE). The emphasis is on basic research in laboratory animals and is chronological, starting with hypotheses that attracted a lot of attention in the 1980s. Then experiments are described that addressed the questions, as well as new methods that often made the experiments possible. In addition, where new questions arose and the implications for clinical epilepsy are discussed.

Keywords: HIPP cell; adult neurogenesis; hilus; mossy cell; mossy fiber sprouting; seizure.

Figure 1.

Concepts underlying epileptogenesis in TLE from the past and present. (A) Past concepts. 1. General timeline. Epileptogenesis had been suggested to occur in 3 phases, the first typically occurring in early life and involving a brain insult or injury. A “silent” period follows the insult or injury and occurs before the first convulsive seizure. The first convulsive seizure is the start of the phase called chronic epilepsy or simply “epilepsy”. 2. Underlying events. The brain insult is typically an acquired event such as brain injury or infection, with examples listed. During the silent period, MTS develops and ultimately recurrent spontaneous seizures (defining chronic epilepsy). (B) Present concepts. 1. The general timeline is now considered with more appreciation for the role of genes. Therefore, after an initial insult or after altered genes exert effects (eg, on neurodevelopment), there is a progressive worsening of increased excitability (epileptogenesis). Spontaneous seizures can occur early or later in this progressive course of events. After 2 unprovoked seizures the term epilepsy is used 2. Underlying events. Initial events include those that are not acquired. There is a rapid start in the reaction of the brain to the insult and ultimately a complex series of events unfolds, with some reactions leading to further changes. TMTS is one of the events that stimulates changes but others can also. Spontaneous recurrent seizures may occur before the brain stops changing.

Figure 2.

Past and present perspectives on the role of the dentate gyrus (DG) in temporal lobe epilepsy (TLE). A. Past views. A simplified schematic of the DG in TLE is shown with the major layers on the left (MOL, molecular layer; GCL, granule cell layer; HIL, hilus). Glutamatergic neurons are green; GABAergic neurons are red. In TLE, hilar MCs and SOM cells are reduced (dotted lines). The axons of GCs sprout in the epileptic brain and innervate dendrites in the MOL (SPROUT). B. Present views. An updated schematic shows that some MCs and SOM cells are lost in TLE. In addition to reactive astrocytes in the hilus, there are microglia, reflecting new appreciation of the diverse roles of glia and inflammation. New branches of blood vessels emerge because of new appreciation of angiogenesis in TLE. There are progenitors (IMM for immature) in the area next to the GCL which can divide in adulthood, giving rise to new GCs. Ectopic GCs (EGC) arise in the hilus. They contribute to sprouting that previously had been considered to be a characteristic only of cells in the GCL. Immature GCs arise from progenitors that are mainly beneath the GCL but can be in the hilus. Many types of GABAergic neurons (red) are added to the diagram because of the greater understanding that they normally are present. GABAergic neurons are named using a different classification system. PV (parvalbumin) or perisomatic-targeting neurons replace the term basket cells; HIPP cells replaces SOM cells.