Granule cell dispersion (GCD) is a common pathological feature observed in the
hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms
underlying GCD remain to be elucidated, but one hypothesis proposes aberrant
reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile
seizures. This study aims to compare the proteomes of basal and dispersed granule
cells in the hippocampus of eight MTLE patients with GCD to identify proteins that
may mediate GCD in MTLE. Quantitative proteomics identified 1,882 proteins, of which
29% were found in basal granule cells only, 17% in dispersed only and 54% in both
samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples
were involved in developmental cellular migratory processes, including cytoskeletal
remodeling, axon guidance and signaling by Ras homologous (Rho) family of GTPases
(P < 0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently
explored in immunohistochemical and in situ hybridization studies involving eighteen
MTLE cases with or without GCD, and three normal post mortem cases. In cases with
GCD, most dispersed granule cells in the outer-granular and molecular layers have an
elongated soma and bipolar processes, with intense RhoA immunolabeling at opposite
poles of the cell soma, while most granule cells in the basal granule cell layer were devoid
of RhoA. A higher percentage of cells expressing RhoA was observed in cases with GCD
than without GCD (P < 0.004). In GCD cases, the percentage of cells expressing RhoA
was significantly higher in the inner molecular layer than the granule cell layer (P < 0.026),
supporting proteomic findings. In situ hybridization studies using probes against RHOA
and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs was significantly higher in the inner
molecular layer of cases with GCD than without GCD (P = 0.05). In summary, our
study has found limited evidence for ongoing adult neurogenesis in the hippocampus of
patients with MTLE, but evidence of differential dysmaturation between dispersed and
basal granule cells has been demonstrated, and elevated expression of Rho GTPases
in dispersed granule cells may contribute to the pathomechanisms underpinning
GCD in MTLE