RETRACTED: Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice

Abstract

In the developing hippocampus, fibroblast growth factor (FGF) 22 promotes the formation of excitatory presynaptic terminals. Remarkably, FGF22 knockout (KO) mice show resistance to generalized seizures in adults as assessed by chemical kindling, a model that is widely used to study epileptogenesis (Terauchi et al., 2010). Repeated injections of low dose pentylenetetrazol (PTZ) induce generalized seizures (“kindled”) in wild type (WT) mice. With additional PTZ injections, FGF22KO mice do show moderate seizures, but they do not kindle. Thus, analyses of how FGF22 impacts seizure susceptibility will contribute to the better understanding of the molecular and cellular mechanisms of epileptogenesis. To decipher the roles of FGF22 in the seizure phenotype, we examine four pathophysiological changes in the hippocampus associated with epileptogenesis: enhancement of dentate neurogenesis, hilar ectopic dentate granule cells (DGCs), increase in hilar cell death, and formation of mossy fiber sprouting (MFS). Dentate neurogenesis is enhanced, hilar ectopic DGCs appeared, and hilar cell death is increased in PTZ-kindled WT mice relative to PBS-injected WT mice. Even in WT mice with fewer PTZ injections, which showed only mild seizures (so were not kindled), neurogenesis, hilar ectopic DGCs, and hilar cell death are increased, suggesting that mild seizures are enough to induce these changes in WT mice. In contrast, PTZ-injected FGF22KO mice do not show these changes despite having moderate seizures: neurogenesis is rather suppressed, hilar ectopic DGCs do not appear, and hilar cell death is unchanged in PTZ-injected FGF22KO mice relative to PBS-injected FGF22KO mice. These results indicate that FGF22 plays important roles in controlling neurogenesis, ectopic migration of DGCs, and hilar cell death after seizures, which may contribute to the generalized seizure-resistant phenotype of FGF22KO mice and suggests a possibility that inhibition of FGF22 may alleviate epileptogenesis.

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

“…Unbalanced excitation-inhibition has behavioral consequences: Fgf22-KO and Fgf7-KO mice have altered epileptic seizure susceptibility (Terauchi et al, 2010;Lee et al, 2012;Lee and Umemori, 2013). Additionally, other FGFs have also been implicated in epilepsy (Paradiso et al, 2013).…”

“…In the hippocampus, two fibroblast growth factors (FGFs), FGF22 and FGF7, are secreted from dendrites of CA3 pyramidal neurons, and promote differentiation of excitatory and inhibitory presynaptic terminals, respectively (Terauchi et al, 2010(Terauchi et al, , 2015. That this FGF-dependent regulation of excitatory and inhibitory presynaptic differentiation is important for proper brain development is evidenced by altered seizure susceptibility of knockout (KO) animals: Fgf22-KO mice have decreased, and Fgf7-KO mice have increased susceptibility to epileptic seizures (Terauchi et al, 2010;Lee et al, 2012;Lee and Umemori, 2013). However, the signaling mechanisms underlying FGF-dependent synapse formation are currently not understood.…”

Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network

“…Our lab found that FGF22KO animals have lower levels of adult neurogenesis as measured by the number of doublecortin-positive cells in the SGZ (which marks immature granule cells), without a significant decrease in proliferating cells (as measured by Ki67) or in the gross morphology of the dentate gyrus. 15 This suggests that FGF22 is required for differentiation or maintenance of newly born neurons in the adult dentate gyrus.…”

“…Specifically, neurotransmitter-laden synaptic vesicles fail to accumulate at excitatory or inhibitory presynaptic-terminals in FGF22 knockout (KO) and FGF7KO mice, respectively, which in turn leads to decreased excitatory or inhibitory synaptic efficacy. Dysregulation of FGF22 or FGF7 has pathological consequences-FGF22KO mice have decreased excitatory drive in the CA3 and are resistant to developing epileptic seizures using a kindling protocol, 14,15 while FGF7KO mice have decreased inhibitory tone and have increased susceptibility to kindled epileptic seizures. 14,16 The specificity of FGF22 and FGF7 in directing excitatory versus inhibitory presynaptic differentiation is regulated on numerous levels, including through the postsynaptic localization of FGF22 at nascent excitatory and FGF7 at nascent inhibitory synapses along CA3 dendrites, 14,17 and through utilization of distinct sets of FGF receptors (FGFRs) in the presynaptic axon-terminals.…”

Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice

“…When FGF22 is deleted in mice (FGF22KO mice), excitatory synapses in the hippocampus fail to form during development, and this defect persists into adulthood (1). The deletion of FGF22 renders mice resistant to seizure kindling in a pentylenetetrazol (PTZ) kindling model of epilepsy (1), and FGF22KO mice do not display seizure-induced neuropathology, such as increased hippocampal mossy fiber sprouting and hilar cell death, even when seizures are induced (7). FGF22 has been implicated in the organization of other excitatory synapses in the brain, including retinogeniculate synapses (8) and mossy fiber-dentate granule cell synapses in the cerebellum (3), as well as the peripheral neuromuscular junction (NMJ) synapse (9).…”