Abstract
Accumulation of amyloid β oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether AβO causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in AβO-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in AβO-injected mice selectively restored AβO-induced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from AβO-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus–response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that AβO increased the initial GABA release probability to depress SST/PV interneuron’s inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons’ input to CA1 PC as the synaptic mechanisms underlying AβO-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by progressive memory loss and cognitive decline (LaFerla et al 2007; Selkoe 2002; Hardy and Selkoe 2002)
We found that the peak power of theta oscillations that was significantly reduced in amyloid β oligomers (AβO)-injected SSTCre mice was fully restored by the optogenetic activation of SST interneurons (Fig. 1o) without affecting the peak frequency of theta oscillations (Fig. 1p), while there was no effect on peak powers nor peak frequencies of delta, beta, and gamma oscillations (Fig. 1q, r; Online resource Fig. 2)
The major advantage of using the AβO-injection mouse model of AD was that we were able to perform optogenetic activation of SST and PV interneurons in cre-transgenic animals. Using this AD mouse model, we showed, for the first time, that sustained optogenetic activation of SST and PV interneurons could selectively restore the power of hippocampal theta and gamma oscillations impaired by AβO pathology in vivo, respectively, (Figs. 1, 2) without affecting other frequencies such as delta and beta oscillations (Online resource Fig. 2), and resynchronize the CA1 pyramidal cell (PC) spike phases relative to both theta and gamma oscillations to the level observed in the control mice (Fig. 3)
Summary
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by progressive memory loss and cognitive decline (LaFerla et al 2007; Selkoe 2002; Hardy and Selkoe 2002). Recent experimental evidence revealed that SST and PV interneurons disintegrate structurally and functionally in mouse models of AD (Palop et al 2007; Schmid et al 2016; Chen et al 2018; Verret et al 2012; Martinez-Losa et al 2018; Iaccarino et al 2016), suggesting that dysfunctions of SST and PV interneurons may underlie impairments of theta and gamma oscillations observed in AD. Optogenetic activation (Iaccarino et al 2016) or molecular manipulation (Martinez-Losa et al 2018; Zhang et al 2017) of PV interneurons could restore impaired hippocampal gamma oscillations in mouse models of AD. The relative contribution of SST and PV interneurons to the impairments of hippocampal theta and gamma oscillations observed in AD remains unknown
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