Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Abstract

Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells undergo mossy fiber sprouting in the dentate gyrus which contributes to a recurrent, proepileptogenic circuitry in the hippocampus. Here it is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions. Using the intrahippocampal kainate mouse model for MTLE and the CA2-specific markers Purkinje cell protein 4 (PCP4) and regulator of G-Protein signaling 14 (RGS14), it was found that during epileptogenesis CA2 neurons survive and disperse in direction of CA3 and CA1 resulting in a significantly elongated CA2 region. Using transgenic mice that express enhanced green fluorescent protein (eGFP) in granule cells and mossy fibers, we show that the recently described mossy fiber projection to CA2 undergoes sprouting resulting in aberrant large, synaptoporin-expressing mossy fiber boutons which surround the CA2 pyramidal cell somata. This opens up the potential for altered synaptic transmission that might contribute to epileptic activity in CA2. Indeed, intrahippocampal recordings in freely moving mice revealed that epileptic activity occurs concomitantly in the dentate gyrus and in CA2. Altogether, the results call attention to CA2 as a region affected by MTLE-associated pathological restructuring.

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

“…Previous animal studies attributed increased diffusivity and anisotropy to mossy fiber sprouting (Kharatishvili et al, 2007; Parekh et al, 2010) and reorganization of myelinated fibers (Laitinen et al, 2010), but in these studies histological validation was performed only in the chronic stage of epilepsy. Our histological analysis expands this view revealing that significant mossy fiber sprouting is restricted to the later stages of epileptogenesis (around 14 days onward), which is consistent with previous observations for the CA2 region (Häussler et al, 2016). Although it is well conceivable that mossy fiber sprouting alters DWI metrics during this period, earlier changes (4 to 14 days) particularly of AD and dvD likely correspond to radial gliosis.…”

Rediscovering area CA2: unique properties and functions

“…Finally, a recent report has detailed another possible mechanism underlying epileptic activity in a mouse model of TLE 127 . Following kainate injection into the hippocampus, CA2 pyramidal neurons not only survived in far greater numbers than CA3 and CA1 pyramidal neurons, but they also appeared to disperse and take over territory once occupied by neurons in areas CA1 and CA3.…”

“…Following kainate injection into the hippocampus, CA2 pyramidal neurons not only survived in far greater numbers than CA3 and CA1 pyramidal neurons, but they also appeared to disperse and take over territory once occupied by neurons in areas CA1 and CA3. In addition, the mossy fibres were found to sprout into the CA2 SP, forming synapses on CA2 pyramidal neuron somata 127 . This study further demonstrates that neurons in the DG and area CA2 support epileptic activity, suggesting that growth of this aberrant circuitry might underlie, in part, the development of TLE.…”

Organization and control of epileptic circuits in temporal lobe epilepsy

“…Adult granule cells sprout most commonly to the inner molecular layer of the dentate gyrus to synapse upon other granule cells. They also form new synapses onto granule cells in the granule cell layer, ectopic granule cells in hilus, aberrant granule cell basal dendrites in the hilus, hilar cells, and pyramidal cells of CA2 and CA3 (Haussler et al, 2016; Parent et al, 1997). Finally, connections between sprouted mossy fibers and interneurons have been observed, but the functional consequence of this finding is controversial (Buckmaster, 2012; Wenzel et al, 2000).…”