Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders

Abstract

Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia.

Figure 1

(a) Under normal conditions, mossy fibers and axons of granule cells target the SL region in the CA3 subfield, forming SPB. Contrastingly, a pathological condition occasionally results in ectopic mossy fiber projection, in which axons are guided not only to the SL, but also to the SO. (b) During postnatal development, both SPB and IPB are formed. Mossy fibers projected to the SO undergo retraction, thus leaving only SPB as they mature. (c) Presented are immune fluorescent staining of Znt-3 in the hippocampal sections. In α-CaMKII hKO mice, mossy fibers display robust projection onto the SO, developing IPB as indicated by arrowheads.

Figure 2

Upon maturation of newborn granule cells in neurons, excess amounts of BDNF possibly induce branching of mossy fibers towards the SO, and exacerbated fasciculation may occur in α-CaMKII hKO mice. Retraction of mossy fiber axons in the SO fails due to high expression of PSA on NCAM, thus displaying persistent presence of ectopic mossy fiber projection.

Figure 3

A schematic representation of the shared pathophysiology from genetic level to behavior level across α-CaMKII hKO mice, psychiatric patients, and patients with TLE. A mutation of CAMK2A gene was found in patients with schizophrenia and it is also implicated in bipolar disorder [72, 73]. α-CaMKII hKO mice have behavioral deficits [63] which are observed in patients with schizophrenia and TLE [74, 75]. Furthermore, α-CaMKII hKO animals were shown to have immaturation of granular cells in DG which was also observed in patients [74]. Importantly, the α-CaMKII hKO mouse showed the neuronal hyperactivity [63, 64] that matches to the observed hyperactivity in the hippocampus in patients [33, 38, 65, 66]. These shared features and the having history of febrile seizure in patients lead us to hypothesize the presence of mossy fiber misguidance [76] in patients with schizophrenia.