Expression of Synaptopodin, an Actin‐associated Protein, in the Rat Hippocampus after Limbic Epilepsy

Abstract

Synaptopodin, a 100 kD protein, associated with the actin cytoskeleton of the postsynaptic density and dendritic spines, is thought to play a role in modulating actin-based shape and motility of dendritic spines during formation or elimination of synaptic contacts. Temporal lobe epilepsy in humans and in rats shows neuronal damage, aberrant sprouting of hippocampal mossy fibers and subsequent synaptic remodeling processes. Using kainic acid (KA) induced epilepsy in rats, the postictal hippocampal expression of synaptopodin was analyzed by in situ hybridization (ISH) and immunohistochemistry. Sprouting of mossy fibers was visualized by a modified Timm's staining. ISH showed elevated levels of Synaptopodin mRNA in perikarya of CA3 principal neurons, dentate granule cells and in surviving hilar neurons these levels persisted up to 8 weeks after seizure induction. Synaptopodin immunoreactivity in the dendritic layers of CA3, in the hilus and in the inner molecular layer of the dentate gyrus (DG) was initially reduced. Eight weeks after KA treatment Synaptopodin protein expression returned to control levels in dendritic layers of CA3 and in the entire molecular layer of the DG. The recovery of protein expression was accompanied by simultaneous supra-and infragranular mossy fiber sprouting. Postictal upregulation of Synaptopodin mRNA levels in target cell populations of limbic epilepsy-elicited damage and subsequent Synaptopodin protein expression largely co-localized with remodeling processes as demonstrated by mossy fiber sprouting. It may thus represent a novel postsynaptic molecular correlate of hippocampal neuroplasticity.

Synaptopodin Regulates Plasticity of Dendritic Spines in Hippocampal Neurons

“…These observations indicate that SP is associated with mature spines and that synaptic innervations may contribute to the targeting and maintenance of SP in dendritic spines. The results are consistent with studies which show lamina-specific alterations in the distribution of SP in the hippocampus after denervation (Deller et al, 2006) and after synaptic stimulation (Roth et al, 2001;Yamazaki et al, 2001;Fukazawa et al, 2003).…”

“…In previous studies a massive activation of intact tissue using kainic acid caused an increase in SP mRNA in the somata of hippocampal neurons (Roth et al, 2001). Likewise, tetanic stimulation which produces LTP caused a rise in SP mRNA in the dentate gyrus of the intact animal (Yamazaki et al, 2001).…”

Hippocampal seizures cause depolymerization of filamentous actin in neurons independent of acute morphological changes

“…We found that seizure activity causes activation (dephosphorylation) of cofilin and an associated depolymerization of F-actin, even in the absence of major structural changes to the dendrites. While a recent study found that disruption of actin networks may alter seizure threshold (SierraParedes et al, 2006) and other studies indicate that seizures may affect actin-binding proteins (Roth et al, 2001;Ferhat et al, 2003), the present study is among the first to directly show that seizures can modulate actin polymerization, as well as cofilin activation. While it is possible that the actin depolymerization might be a direct pharmacological effect of 4-AP rather than the seizure activity, preliminary data from our and other labs suggest similar effects in other seizure models (Wong, unpublished data), and p-cofilin was decreased bilaterally in this study, despite a unilateral 4-AP injection, consistent with seizure-mediated actions.…”

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

“…Recent evidence suggests that specific calcium-activated enzymes, such as calcineurin, are activated in animal models of epilepsy [86]. Furthermore, actin and actin-associated proteins are regulated by acute seizures or during chronic epileptogenesis [75,87,88]. In particular, seizures lead to acute depolymerization of filamentous actin, which could directly account for structural changes in dendrites [75].…”