Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

Abstract

Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer's disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

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

“…However, unlike previous studies using animal models with the late phase of Alzheimer's disease [5,7,8], the acute effects of AβO 1-42 that we uncovered here may only account for the early phase of Alzheimer's disease. In Alzheimer's disease mouse models such as APP/PS1 mice [40] and hAPPJ20 mice [5], spike firing rates and membrane potentials of PV interneuron are increased while in early phase of Alzheimer's disease, pathological effects of AβO 1-42 are mainly limited to synaptic dysfunctions with the intrinsic neuronal properties are spared [41], which is consistent with our results (Figs. 2 and 3 and Additional file 4: Figure S4).…”

Changes in neuronal excitability and synaptic transmission in nucleus accumbens in a transgenic Alzheimer’s disease mouse model

“…However, given that AMPA transmission was also affected, a question of how is it that the decrease in both neurotransmissions (excitatory and inhibitory), with opposite effects, can contribute to an increase in neuronal excitability? Impairment of excitatory and inhibitory synaptic transmission may indeed be involved in the altered neuronal excitability, as previously reported in the hippocampus and cortex of AD models [64][65][66][67][68][69] . However, it is unclear whether changes in excitatory/inhibitory drive in AD mouse models represents a compensatory mechanism for hyperexcitability, or vice versa.…”

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

“…Moreover, nicotine enhanced synaptic plasticity in the CA3-CA1 synapses, and GABA receptor antagonists inhibited this enhancement, suggesting that GABAergic interneurons are required for nicotine-treated adult anti-NGF mice (AD11), a comprehensive animal model of AD (Rosato-Siri et al, 2006). However, recent studies demonstrated that at the early stage of AD (16 weeks), Aβ induces hyperexcitability of hippocampal PV interneurons and contributes to neural network dysfunction and memory impairment in APP/PS1 mice (Hijazi et al, 2019). Suppressing PV interneuron hyperexcitability restored PV interneuron properties to wild-type levels, thereby reducing inhibitory inputs into pyramidal cells and rescuing memory deficits (Hijazi et al, 2019).…”

“…However, recent studies demonstrated that at the early stage of AD (16 weeks), Aβ induces hyperexcitability of hippocampal PV interneurons and contributes to neural network dysfunction and memory impairment in APP/PS1 mice (Hijazi et al, 2019). Suppressing PV interneuron hyperexcitability restored PV interneuron properties to wild-type levels, thereby reducing inhibitory inputs into pyramidal cells and rescuing memory deficits (Hijazi et al, 2019). One possible reason for the discrepancy may be due to the different ages and models of mice used in different studies.…”