Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

Abstract

Temporal lobe epilepsy in both animals and humans is characterized by abnormally integrated hippocampal dentate granule cells. Among other abnormalities, these cells make axonal connections with inappropriate targets, grow dendrites in the wrong direction and migrate to ectopic locations. These changes promote the formation of recurrent excitatory circuits, leading to the appealing hypothesis that these abnormal cells may by epileptogenic. While this hypothesis has been the subject of intense study, less attention has been paid to the possibility that abnormal granule cells in the epileptic brain may also contribute to co-morbidities associated with the disease. Epilepsy is associated with a variety of general findings, such as memory disturbances and cognitive dysfunction, and is often co-morbid with a number of other conditions, including schizophrenia and autism. Interestingly, recent studies implicate disruption of common genes and gene pathways in all three diseases. Moreover, while neuropsychiatric conditions are associated with changes in a variety of brain regions, granule cell abnormalities in temporal lobe epilepsy phenocopy granule cell deficits produced by genetic mouse models of autism and schizophrenia, suggesting that granule cell dysmorphogenesis may be a common factor uniting these seemingly diverse diseases. Disruption of common signaling pathways regulating granule cell neurogenesis may begin to provide mechanistic insight into the co-occurrence of temporal lobe epilepsy and cognitive and behavioral disorders.

Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus

“…It is currently unknown whether these anomalies by themselves are adequate to induce spontaneous seizures (48). Nonetheless, their involvement in manifestations of spontaneous seizures after SE has been well documented (49)(50)(51)(52)(53)(54). We measured reelin + interneurons in the DH to identify the mechanism behind A1-exosome-mediated inhibition of aberrant neurogenesis, as migration of newly born dentate granule cells from the SGZ to GCL is steered by reelin protein secreted by reelin + interneurons in the DH, and considerable loss of these neurons fosters aberrant displacement of newly born neurons into the DH (55).…”

Increased gyrification and aberrant adult neurogenesis of the dentate gyrus in adult rats

“…Other neurons migrate to the GC layer correctly but develop basal dendrites (Spigelman et al 1998; Ribak et al 2012). Other GCs hypertrophy or are abnormal in morphology (Murphy et al 2012; Pun et al 2012; Hester and Danzer 2014). The current study also suggests that in the most posterior sections of the DG there is an accumulation of immature neurons in gyri and this abnormal spatiotemporal distribution increases as the time after SE increases so that the primary site where immature neurons exists is large gyri, at least for the most posterior parts of the hippocampus.…”

“…There is a dramatic increase in proliferation after SE, originally shown by Parent et al (1997). Many of the newly born GCs develop impairments in structure, location and integration into the preexisting circuitry (Scharfman 2004; Overstreet-Wadiche et al 2006b; Shapiro et al 2008; Zhao and Overstreet-Wadiche 2008; Hester and Danzer 2014; Jessberger and Parent 2015). Another structural change is the growth of collaterals or ‘sprouting’ of the axons of GCs (Nadler 2003; Sutula and Dudek 2007; Buckmaster 2012), which often arise from abnormal adult-born neurons (Scharfman et al 2000; Pierce et al 2011).…”

Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain

“…The mechanisms by which rapamycin produces these positive effects, however, are unclear. For the present study, we examined several hippocampal abnormalities implicated in the development of temporal lobe epilepsy (Parent and Kron, 2012; Hester and Danzer, 2014), including mossy fiber sprouting (Buckmaster, 2014), hilar ectopic granule cell accumulation (Scharfman and Pierce, 2012), basal dendrite formation (Ribak et al, 2012), reactive astrogliosis and microgliosis (Sharma et al, 2008; Gibbons et al, 2013) and mossy cell loss (Jinde et al, 2013). Consistent with previous studies (Zeng et al, 2009; Buckmaster et al, 2009), we observed a significant reduction in mossy fiber sprouting with rapamycin treatment.…”