Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid β oligomers

Abstract

Background: Abnormal accumulation of amyloid β 1-42 oligomers (AβO 1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AβO 1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AβO 1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. Results: Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AβO 1-42 causes synapse-specific dysfunction in PV and SST interneurons. AβO 1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AβO 1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AβO 1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. Conclusions: Our results reveal that AβO 1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.

Dissociation of somatostatin and parvalbumin interneurons circuit dysfunctions underlying hippocampal theta and gamma oscillations impaired by amyloid β oligomers in vivo

“…p > 0.05), and one-way ANOVA followed by Tukey's post hoc test (p, ***p < 0.001, **p < 0.01). Data are mean ± SEM with individual data values (dots) ◂ oscillations could be in part explained by additional excitation provided by optogenetic activation of SST/PV interneurons allowing for the activation of SST/PV interneuronal networks to a critical level for oscillations, which would otherwise show reduced activation due to the AβO-induced decrease in the excitation level in SST and PV interneurons (Hanson 2017;Schmid et al 2016;Park et al 2020). Indeed, optogenetic activation of SST and PV interneurons restored the sIPSC amplitudes to the level observed in DMSOinjected mice (Fig.…”

“…Soluble AβO was prepared following the methods described in (Lambert et al 1998) with slight modification in Aβ oligomerization (Park et al 2020). Soluble Aβ 1-42 (Bechem) monomerization was achieved by dissolving it in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, Sigma Aldrich) at a final concentration of 1 mM.…”

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

“…Improving Nav1.1 expression (Verret et al, 2012), enhancing γ-oscillatory activity in PV inhibitory interneurons by 40 Hz light flickering with/without 40 Hz auditory stimulation (Iaccarino et al, 2016;Adaikkan et al, 2019;Martorell et al, 2019), or transplanting Nav1.1-overexpressing interneurons (Verret et al, 2012;Martinez-Losa et al, 2018) could inhibit epileptiform phenomena and rescue cognitive deficits. Optogentic activation of PV and SST neurons rescued network oscillations (Chung et al, 2020;Park et al, 2020).…”

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

“…In further support of a link between PV interneurons and symptoms of PICS, we found that theta or gamma oscillation, a neurophysiological phenomenon that is supported by PV interneuron function, correlates positively with time with novel object. In one recent study, it is reported that PV and SST interneurons play a key role in hippocampal theta-nested gamma oscillations and long-term potentiation [41]. This is further supported by findings that changes in cortical gamma oscillation power and/or frequency can lead to various behavioral and cognitive effects [26,39].…”