Early detonation by sprouted mossy fibers enables aberrant dentate network activity

Abstract

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an "early detonation" mode and an increased probability of release compared to mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release thus facilitating reverberant circuit activity. Significance StatementSprouted mossy fibers are one of the hallmark histopathological findings in temporal lobe epilepsy. These fibers form recurrent excitatory synapses onto other dentate granule cells that display profound short-term depression. Here, however, we show that although these sprouted mossy fibers weaken substantially during repetitive activation, their initial high probability of glutamate release can activate reverberant network activity. Furthermore, we find that a lack of tonic adenosine inhibition enables this high probability of release and, consequently, recurrent network activity.

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

“…In addition, at the DG → CA2 circuit we observed a substantial increase in short-term depression that could reflect an elevated presynaptic release probability (supp. figure 3), as reported previously at synapses formed by sprouted mossy fibers (Hendricks, Chen, Bensen, Westbrook, & Schnell, 2017; Hendricks, Westbrook, & Schnell, 2019). At the CA2 → CA1c deep circuit we found short-term synaptic potentiation not seen in control tissue (figure 6C - E).…”

Long‐term outcome in a noninvasive rat model of birth asphyxia with neonatal seizures: Cognitive impairment, anxiety, epilepsy, and structural brain alterations

“…35,36,65,66 More recent preclinical studies suggest that the new (synaptoporin-positive) neurites establish functional synaptic connections and may contribute to the state of hyperexcitability that either provokes or facilitates abnormal discharges. 35,67 In a hypoxiaonly model of neonatal seizures, aberrant MFS was observed in the stratum oriens of the CA3 hippocampal region, 62,68 similar to the MFS in the present model. The altered mossy fiber distribution was a likely explanation of the enhanced synaptic activity seen at CA1:CA3 synapses following neonatal seizures 69 and the disturbance in cognitive function seen in later life.…”

Connectivity and Neuronal Synchrony during Seizures

“…This connectivity hypothesis is further supported by earlier observations that mossy fiber sprouting extends septotemporally for 600-700 mm in chronic models of kainic acid and kindling, connecting lamella which normally have little or no connectivity (Sutula et al, 1998). The formation of excitatory "detonator" sprouted mossy fiber synapses has recently been demonstrated to potentially contribute to recurrent excitation across septotemporal lamella (Hendricks et al, 2019).…”