Epilepsy and Adult Neurogenesis

Seizure activity in the hippocampal region strongly affects stem cell-associated plasticity in the adult dentate gyrus. Here, we describe how seizures in rodent models of mesial temporal lobe epilepsy (mTLE) affect multiple steps in the developmental course from the dividing neural stem cell to the migrating and integrating newborn neuron. Furthermore, we discuss recent evidence indicating either that seizure-induced aberrant neurogenesis may contribute to the epileptic disease process or that altered neurogenesis after seizures may represent an attempt of the injured brain to repair itself. Last, we describe how dysfunction of adult neurogenesis caused by chronic seizures may play an important role in the cognitive comorbidities associated with mTLE.The epilepsies are a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures. Some epilepsies result from inherited mutations in single or multiple genes, termed idiopathic or primary epilepsies, whereas symptomatic or secondary epilepsies develop as a consequence of acquired brain abnormalities, such as from tumor, trauma, stroke, infection, or developmental malformation. Of acquired epilepsies, mesial temporal lobe epilepsy (mTLE) is a particularly common and often intractable form. In addition to pharmacoresistant seizures, the syndrome of mTLE almost always involves impairments in cognitive function (Helmstaedter 2002; Elger et al. 2004; von Lehe et al. 2006) that may progress even with adequate seizure control (Blume 2006).Seizure activity in mTLE subjects typically arises from the hippocampus or other mesial temporal lobe structures. Simple and complex partial seizures, the most common seizure types in this epilepsy syndrome, often become medically refractory and may respond only to surgical resection of the epileptogenic tissue. Patients usually also have secondarily generalized tonic–clonic seizures, although these are often controlled by anticonvulsants. Hippocampi in pharmacoresistant mTLE usually show substantial structural abnormalities that include pyramidal cell loss, astrogliosis, dentate granule cell axonal reorganization (mossy fiber sprouting), and dispersion of the granule cell layer (GCL) (Blumcke et al. 1999, 2012).Humans with mTLE often have a history of an early “precipitating” insult, such as a prolonged or complicated febrile seizure, followed by a latent period and then the development of epilepsy in later childhood or adolescence. These historical findings have led to the development of what are currently the most common animal models, the status epilepticus (SE) models, used to study epileptogenic mechanisms in mTLE. In these models, a prolonged seizure induced by chemoconvulsant (typically kainic acid or pilocarpine) treatment or electrical stimulation leads to an initial brain injury, followed, after a latent period of days to weeks, by spontaneous recurrent seizures. These models recapitulate much of the pathology of human mTLE (reviewed in Buckmaster 2004). Experimental paradigms are necessary to investigate mechanisms underlying mTLE, as surgical specimens from mTLE cases are collected at late stages of the disease and, thus, are unlikely to reveal early features critical for the disease process. Studies of experimental mTLE indicate that excess neural activity in the course of seizures not only damages existing, mature structures of the hippocampal formation but also dramatically affects endogenous neural stem cells (NSCs) within the adult rodent dentate gyrus (Bengzon et al. 1997; Parent et al. 1997; Scott et al. 1998). In the following, we will discuss the consequences of seizure activity on proliferation of NSCs, maturation and integration of newborn neurons, and the functional relevance of seizure-induced neurogenesis.