Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

Abstract

Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer’s Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.

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

“…We show that activating PV neurons at 24 weeks of age had similar beneficial effects on hippocampal learning and memory as inhibiting PV neurons at 16 weeks of age. These data support biphasic alterations in PV neuron activity in APP/PS1 mice, in which early hyperexcitability of PV interneurons may result in hypoactivity at a later stage, a mechanism that has been proposed for AD previously [45,50] and reported for other neurodegenerative diseases as well [62]. These findings are also consistent with previous studies showing that increasing GABAergic transmission can restore network function in different mouse models of AD [24,61,63], assuming that the hypoactive stage of PV neurons was targeted in these studies.…”

“…Although the amyloid cascade hypothesis has been leading in AD research over the past 30 years, it is still not clear how Aβ initiates AD-associated neuronal network dysfunction and cognitive impairment. Aberrant inhibitory synaptic transmission is increasingly recognized as an important factor in early AD pathogenesis [12,24,29,45,46], and PV interneurons in particular have been identified as a potential source of impaired inhibitory transmission in mouse models of AD [10,27,28,38,50] alterations in AD. In addition, our data show that the hyperexcitability of PV interneurons in APP/PS1 mice coincides with an increase in spontaneous inhibitory inputs onto hippocampal CA1 pyramidal neurons.…”

Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

“…These disturbances occur in cardiovascular diseases and, perhaps, aging and Alzheimer’s disease. 23–25,89 They occur as well in mitochondrial diseases associated with impaired mitochondrial function and oxidative stress. 26–28…”

“…Since gamma oscillations are known to be associated with selective attention, memory formation, and sensory perception (Buzsáki and Draguhn, 2004;Colgin, 2016;Colgin and Moser, 2010;Paulsen and Moser, 1998;Uhlhaas and Singer, 2010), it is not surprising that disturbances in gamma oscillations are observed in many brain disorders. This includes AD (Hidisoglu et al, 2018;Hollnagel et al, 2019), schizophrenia (Hamm et al, 2017), ischemia (Barth and Mody, 2011), psychosis (Ahnaou et al, 2017), and depression (Fitzgerald and Watson, 2018). The question remains in these diseases, whether alterations of gamma oscillations are a by-product or are contributing to cognitive impairments.…”

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

“…Currently, more in-depth research is being conducted in different mice strains regarding gene alterations that occur in AD, such as the changes present in the TgCRND8 mice, which are related to cholinergic neuron dysfunction and have found differences between this strain and the wild type in regards to actively translating mRNAs in anterior forebrain cholinergic [114], which could help us develop new strains closer in resemblance to that of AD patients [113]. Other models such as APPPS1 mice [115] or 3xTg-AD are being explored or are currently used in laboratory testing [116].…”