Increased Hippocampal Excitability in the 3xTgAD Mouse Model for Alzheimer's Disease In Vivo

Abstract

Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Moreover, our findings support recent studies in humans and rodent models linking hippocampal overactivity and hyperexcitability to age-related memory deficits (Koh et al 2010;Bakker et al 2012;Davis et al 2014) and are consistent with the correlation of hippocampal overactivity with memory deficits in schizophrenia (Tregellas et al 2014). However, hippocampal neural disinhibition may facilitate hippocampal synaptic plasticity and, thereby, improve memory, if such disinhibition is finely and dynamically regulated by endogenous plasticity (Donato et al 2013) or if there is a pre-existing deficit due to increased neural inhibition (Fernandez et al 2007).…”

“…It is entirely consistent with these studies that hippocampal neural disinhibition, which increases hippocampal burst firing and, by way of hippocampo-prefrontal functional connectivity, would modulate prefrontal function, causes similar selective reductions in accuracy on the 5CSRT task. Interestingly, both the pilocarpine rat model (Kumar and Buckmaster 2006) and the triple transgenic mouse model of Alzheimer's disease (Davis et al 2014) show hippocampal hyperexcitability; our new finding that hippocampal neural disinhibition causes attentional impairments suggests that hippocampal hyperexcitability may contribute to the attentional deficits in these rodent models. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 …”

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

“…Hyperexcitability has been described in AD models and patients and can be the trigger for glutamatergic overstimulation (Davis et al, 2014;Friedman et al, 2012;Noebels, 2011;Palop and Mucke, 2009). Pyruvate, in association with 3-beta-hydroxybutyrate, has been shown to reduce epileptiform activity in a AD mouse model (Zilberter et al, 2013).…”

“…Given the enhanced neuronal excitability observed in 3xTg-AD mice in vivo (Davis et al, 2014), we explored whether the phenomenon could be attenuated by pyruvate. To gather information of pyruvate effects on the excitability of our Tg AD cultures, spontaneous activity was investigated in 3xTg-AD cultured neurons by measuring Ca 2+ spikes.…”

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

“…In vitro and animal model studies have demonstrated that Aβ pathology associates with increased excitability of hippocampal neurons, leading to hypersynchronous network activity and higher risk for seizures (Born et al, 2014; Brown et al, 2011; Busche et al, 2012; Davis et al, 2014; Del Vecchio et al, 2004; Minkeviciene et al, 2009; Palop et al, 2007; Putcha et al, 2011). Epidemiologic studies have confirmed comorbidity between patients with AD and epilepsy, showing increased risk of seizures in AD patients (Amatniek et al, 2006; Hommet et al, 2008).…”