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.

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

“…Moreover, DG and CA3 hyperactivity have been implicated in early stages of AD (Bakker et al, 2012). In addition, the DG is considered to be a critical regulator of hippocampal hyperexcitability in epilepsy research (Heinemann et al, 1992; Krook-Magnuson et al, 2015; Lothman et al, 1992; Scharfman, 2019). Notably, our data are consistent with the enhanced expression of markers of neuronal activity observed in GCs in another mouse model of human APP mutations (J20 mice) (You et al, 2017).…”

“…The seizures are easily missed because they are not always accompanied by movement, and epileptiform activity is easily missed because an EEG is not always conducted, or recordings are made far from the site of abnormal activity (Lam et al, 2019). For these reasons and others, there are still many questions about the extent to which hyperexcitability occurs and its importance to AD pathophysiology (Friedman et al, 2012; Leonard and McNamara, 2007; Scarmeas et al, 2009; Scharfman, 2019; Vossel et al, 2017).…”

“…First, several neuroanatomical changes occur in the DG in hAPP mouse models (Bearer et al, 2018; Fontana et al, 2017; Jacobsen et al, 2006; Krezymon et al, 2013; Ohm, 2007; Palop et al, 2005; Palop et al, 2007; Palop et al, 2003; Roberson et al, 2011; You et al, 2017) that also occur in human AD (Ohm, 2007; Scharfman, 2012; Scharfman, 2019). Regarding hyperexcitability, the DG is relevant because it is considered to be a region that can generate seizures in temporal lobe epilepsy (Heinemann et al, 1992; Kobayashi and Buckmaster, 2003; Krook-Magnuson et al, 2015; Lothman et al, 1992; Scharfman, 2019; Sun et al, 2007). In amnestic mild cognitive impairment, neuroimaging shows that the DG and area CA3 are hyperexcitable (Bakker et al, 2012).…”

Ex vivo mesoscopic diffusion MRI correlates with seizure frequency in patients with uncontrolled mesial temporal lobe epilepsy

“…These biomarkers are generally considered unspecific downstream pathological events, rather than putative causative events, such as changes in cellularity in hippocampal layers (Reddy, Younus, Sridhar, & Reddy, 2019; Wiest & Beisteiner, 2019). Although changes in connectivity due to Mossy fiber sprouting have been hypothesized to form a reverberant excitatory network, evidence of this aberrant connectivity in humans remains sparse (Buckmaster, 2014; Modo, Hitchens, Liu, & Richardson, 2016; Scharfman, 2019).…”

Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K+ channel plasticity

“…Anticonvulsant drugs that are effective in controlling epileptic seizures do not necessarily demonstrate efficacy as antiepileptogenic agents. In epileptogenesis, the precursor “latent period” that occurs prior to synchronous and recurrent seizure is no longer viewed as a time of “silence,” but of significance to the progression of epilepsy disease (Scharfman, ). During this time, the hippocampus undergoes significant plasticity in expression and/or function of ion channels, growth factors, receptors and other signaling molecules, increased metabolic demand, as well as changes in synaptic circuitry and behavior (Bernard, ; Dudek & Staley, ; Löscher, ).…”