Regular articleAmyloid-β alters ongoing neuronal activity and excitability in the frontal cortex
Introduction
One of the major features of Alzheimer's disease (AD) is the accumulation and aggregation of amyloid-beta (Aβ) (Hardy and Selkoe, 2002). The various forms of Aβ have been implicated in a number of possible causes of neuronal dysfunction. In neocortex, Aβ plaques have been associated with morphologic changes (Knowles et al., 1999, Koffie et al., 2009, Spires et al., 2005), with elevations of intraneuronal calcium levels (Busche et al., 2008, Kuchibhotla et al., 2008) and with network disruptions (Bero et al., 2012, Stern et al., 2004), but only weakly associated with the progression of dementia and memory impairments (Ingelsson et al., 2004, Lesne et al., 2008). In addition, soluble Aβ has been associated with memory impairments and cognitive deficits (Crimins et al., 2013, Lesne et al., 2006, Lesne et al., 2008), but pre-plaque mice have shown few intrinsic physiological changes (Busche et al., 2008, Rocher et al., 2008, Roder et al., 2003, Shemer et al., 2006).
The effect of Aβ on excitability has been the subject of a number of recent studies (Busche et al., 2008, Grienberger et al., 2012, Gurevicius et al., 2013, Minkeviciene et al., 2009, Palop and Mucke, 2010, Palop et al., 2007). While some have found increased excitability in young, pre-plaque transgenic mice (Gurevicius et al., 2013, Minkeviciene et al., 2009, Palop et al., 2007), others have found no differences in excitability in these neurons but rather found hyperexcitability in old, plaque burdened cortex (Busche et al., 2008, Grienberger et al., 2012). The effects of early and late stages of Aβ neuropathology on neuronal activity and excitability remain unresolved. Here, we measured the effects of elevated Aβ on neuronal activity in single neurons in the intact cortex in the early and advanced stages of Aβ pathology, before and following significant plaque aggregation and increasing levels of soluble Aβ.
During ongoing activity of neocortical pyramidal neurons in vivo the membrane potential fluctuates between the hyperpolarized “Down state” near the resting membrane potential and the relatively depolarized “Up state” (Cowan and Wilson, 1994, Steriade et al., 1993). The membrane potential fluctuations of these neurons correspond to the temporal envelope of the synaptic inputs, filtered by the nonlinear membrane properties of the postsynaptic cells (Cowan and Wilson, 1994, Sachdev et al., 2004, Stern et al., 1997). This spontaneous activity is the background upon which evoked activity is superimposed, and represents the state of the network (Arieli et al., 1996, Azouz and Gray, 1999, Leger et al., 2005, Tsodyks et al., 1999). Therefore, Aβ-induced changes in the network activity will be reflected in changes in the patterns of spontaneous membrane potential fluctuations.
To quantify the functional cellular and network effects of Aβ on excitability and on ongoing activity of neocortical pyramidal neurons, we recorded intracellularly from neurons in the frontal pole of anesthetized APPswe/PS1dE9 mice in vivo. Measurements were made at 2 adult ages: young (2–4 months) and old (9–18 months) mice. Aβ accumulates and aggregates in the neocortex of these mice in an age-dependent manner (Garcia-Alloza et al., 2006). In the younger mice, significant soluble Aβ has accumulated but plaques are still absent or rare. At the older age, significant plaque aggregation has occurred and soluble Aβ continues to increase. The results were compared with those obtained from recordings in age-matched nontransgenic control littermates (“Wild-type”). The use of intracellular recordings in vivo allowed us to directly measure the effects of Aβ on excitability of individual neurons in the intact cortical network. We could therefore distinguish between Aβ-induced changes caused by intrinsic electrical properties of the neurons (i.e., changes in excitability) from those caused by changes in synaptic network properties in the neocortex (i.e., changes in subthreshold membrane potential dynamics).
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Animals
B6C3 mice expressing both the APPswe and PS1dE9 mutant transgenes (Jankowsky et al., 2001) with a mixed background of C57BL/6J and C3H/HeJ were obtained from Jackson Laboratory. In these mice, Aβ accumulates and aggregates in an age-dependent manner. Two age groups were used in this study; mice aged 2–4 months were termed “young”, whereas mice aged 9–18 months were termed “old”. Aged-matched littermates were used as controls. There were 25 females and 12 males (1 unknown) used in this study. No
Results
We measured the evoked and ongoing spontaneous activity of the membrane potentials of 57 frontal pole pyramidal neurons (medial and lateral agranular cortex) from 38 mice that were divided into 4 experimental groups based on age and genotype (i.e., wild type [WT] young, WT old, transgenic [Tg] young, and Tg old; see Section 2.1). Spontaneous subthreshold membrane potential fluctuations were seen in all neurons (Fig. 1A and B). The fluctuations were typical of those observed in identified
Discussion
We have shown that Aβ affects neuronal ongoing activity and excitability in the frontal cortex of APPswe/PS1dE9 transgenic mice. This is the first study to show specific effects of Aβ on excitability at the level of the single neuron in vivo using electrophysiological methods that reveal the subthreshold mechanisms underlying changes in firing behavior. While a number of studies have used calcium imaging and electrophysiological recording to show hyperexcitability in APP cortex (Busche et al.,
Disclosure statement
The authors declare no competing financial interests.
Acknowledgements
The authors thank Professor Moshe Abeles, Professor Israel Nelken, and Professor Bradley T. Hyman for their valuable suggestions. Funding for this study was provided by the National Institute on Aging (AG024238) and the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (688/10).
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