Abstracts

Rationale: Fast Spiking-Basket Cells (FS-BC) are important for generating gamma (40-100 Hz) oscillations which provide a temporal framework for memory encoding. Inputs from accommodating interneurons (AC-INs) modulate FS-BC network rhythms. Epilepsy is associated with alterations in network oscillations and commonly presents with memory dysfunction, suggesting that FS-BC networks may be compromised. This study was conducted to identify changes in synaptic inhibition to FS-BCs after status epilepticus (SE) and their effects on network rhythms.Methods: Paired interneuronal recordings were conducted in hippocampal slices from male rats one week after pilocarpine induced SE and in saline-injected controls. Interneurons were identified based on intrinsic physiology, post-hoc morphology and immunostaining. Computational models of large-scale heterotypic inhibitory networks including biophysically-realistic FS-BC and AC-IN models and excitatory-inhibitory (E-I) networks including granule cells (GCs) and the inhibitory neurons were implemented in NEURON. Networks were driven by theta-modulated current injections.Results: The probability of connections, amplitude, and kinetics of synapses between FS-BCs were not altered after SE. However, the mean amplitude of AC-IN inputs to FS-BCs was reduced after SE (in pA, control: 38.3±11.5, post-SE: 12.9±3.7, 11 pairs each, p<0.05, Mann-Whitney U-test). The decrease in amplitude resulted from a significant reduction in release probability (control: 0.76±0.09; post-SE: 0.39±0.08, n=11 pairs each, P<0.05). Since heterotypic synaptic connections are critical for maintaining theta oscillations in the presence of network gamma rhythms, we examined whether post-SE changes in probability of release (Prelease) at AC-IN synapses to FS-BCs impacts theta-gamma oscillatory coupling. In both interneuronal and E-I networks, implementing the post-SE reduction in synaptic release at AC-IN to FS-BC synapses (Prelease (AC-IN→FS-BC) = 0.3) enhanced the coherence of FS-BC firing. Power spectra of FS-BC-derived local field potentials (LFPs) showed peaks at both theta and gamma frequencies. However, power of the theta peak in FS-BC-derived LFPs was reduced and gamma power was increased in networks with reduced heterotypic inhibition. Moreover, theta-gamma coupling quantified using an entropy-based “modulation index” was significantly reduced in networks including post-SE reduction in Prelease (AC-IN→FS-BC).Conclusions: These results demonstrate a functional reduction in heterotypic synaptic inhibition to FS-BCs following SE resulting from a selective reduction in the release probability at synapses between AC-INs and FS-BCs. In network simulations, decreasing synaptic release probability from AC-IN to FS-BCs enhanced network coherence and gamma power, but reduced theta power and theta-gamma coupling. Thus the functional reduction in heterotypic inhibition of FS-BCs in epileptic networks could contribute to certain co-morbidities including memory dysfunction in epilepsy.