Regular articleReduced firing rates of pyramidal cells in the frontal cortex of APP/PS1 can be restored by acute treatment with levetiracetam
Graphical abstract
Introduction
Network hypersynchrony and altered neural oscillation have been suggested to contribute to the pathophysiology of Alzheimer's disease (AD) and to the accumulation of AD-related amyloid protein (Busche and Konnerth, 2015; Hardy and Selkoe, 2002; Joutsa et al., 2017; Palop and Mucke, 2016). A better understanding of altered neural oscillations in AD could, therefore, provide a target for pharmacological interventions. Even though amyloid plaques and related neuronal loss are among the most significant findings in the postmortem brain of patients with AD, the amount of plaques does not correlate with the severity of dementia (Nagy et al., 1995), and the removal of plaques does not lead to an improvement of memory (Holmes et al., 2008). Intriguingly, amyloid accumulation seems to cause excitatory-inhibitory imbalance at the synaptic level, triggering abnormal patterns at both the single cell and network levels which manifest as epileptiform discharges (Minkeviciene et al., 2009). Simultaneously with amyloid plaque formation, both hyperactive and hypoactive neurons emerge in the hippocampus and cortical areas (Busche et al., 2012, 2008). Less is known about which subpopulations of cells are affected by amyloid accumulation, but it has been proposed that this pathological process is related to persistently decreased resting membrane potential in neocortical pyramidal neurons (Minkeviciene et al., 2009). Similarly, it has been reported that basic biophysical properties of pyramidal neurons in the frontal cortex are intact but external stimulation of these neurons revealed hyperexcitability, indicating a combination of both intrinsic electrical and extrinsic synaptic dysfunctions as mechanisms for activity changes (Kellner et al., 2014). Importantly, aberrant excitatory activity in AD mouse models has also been found to result in a compensatory strengthening of inhibitory circuits which could lead to an overall suppression of neural activity (Palop et al., 2007). Whether these findings apply to in vivo unanesthetized mice needs to be verified.
On the level of neuronal assemblies, the most prominent finding related to amyloid pathology is abnormally high local field potential (LFP) power over a broad frequency range and during a wide variety of behavioral states (Goutagny et al., 2013; Gurevicius et al., 2013; Jin et al., 2018; Pena-Ortega et al., 2012; Verret et al., 2012), which can lead to epileptiform synchronous discharges and generalized seizure activity (Gurevicius et al., 2013; Jin et al., 2018; Lam et al., 2017; Minkeviciene et al., 2009; Palop and Mucke, 2016; Vossel et al., 2013). The mechanism by which aberrant single-cell activity changes into the generalized epileptiform activity of neuronal ensembles is not clear. Traditionally, epileptic seizures have been characterized as hypersynchrony of large neuronal populations leading to the epileptiform state (Jiruska et al., 2013). However, this view has been challenged by the finding that, during epileptic seizures, there are both increases and decreases in firing rates of neurons, many neurons are unchanged and increased tonic GABAergic inhibition is commonly found in absence epilepsy (Cope et al., 2009; Schevon et al., 2012; Truccolo et al., 2011; Wyler et al., 1982). Furthermore, single-cell activity outside the periods of seizures and areas of epileptic foci is more heterogeneous and unsynchronized, and not well characterized (Keller et al., 2010; Truccolo et al., 2011). In addition, to our knowledge, it is not known if amyloid accumulation affecting EEG power in a broad frequency band is also entraining single-cell activity.
In recent years, antiepileptic pharmacological treatments to balance altered neuronal activity as a consequence of amyloid accumulation have become of interest (Cumbo and Ligori, 2010; Ziyatdinova et al., 2015, 2011). An acute dose of levetiracetam reduces abnormal EEG spiking activity in the cortex and the hippocampus of an AD mouse model for 18 hours after administration (Sanchez et al., 2012). Notably, subchronic treatment with levetiracetam has been shown to compensate abnormal hypoactivation in the entorhinal cortex in people with amnestic mild cognitive impairment while simultaneously improving working memory performance (Bakker et al., 2012). Currently, this treatment is under clinical testing although the basic mechanisms of action of levetiracetam in patients with AD are not well understood (Bakker et al., 2015). In animal models, overexpressing amyloid protein, acute levetiracetam treatment reduces abnormal spike activity, and chronic levetiracetam treatment suppresses hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in hippocampal-dependent learning and memory (Sanchez et al., 2012). Levetiracetam has multiple plausible molecular targets including voltage-gated ion currents, synaptic vesicle proteins and the glutaminergic system (Surges et al., 2008).
However, realtively littel is know about the dynamics of neuronal ensembles that give rise to LFP phenomena, excitatory/inhibitory imbalances as a consequence of amyloid pathology and compensatory effects of drugs such as levetiracetam. To investigate these questions, we recorded both LFP and single-cell activity in 4 head-fixed APP/PS1 mice and 3 wild-type (WT) controls and analyzed the effect of acute levetiracetam treatment. We found that while LFP oscillations showed a power increase in the theta and beta frequency range as previously reported, frontal cortex pyramidal cell firing rates were significantly reduced in APP/PS1 mice. At the same time, the sparsely firing pyramidal cells phase-locked more strongly to the ongoing theta rhythm. Treatment of APP/PS1 mice with levetiracetam specifically elevated pyramidal cell firing rates and uncoupled pyramidal cells and interneurons as shown by decreased pairwise correlations.
In summary, our results indicate that reduced firing rates of cortical pyramidal cells emerge as a symptom of amyloid pathology and that treatment with levetiracetam might be a viable approach to reverse this abnormal activity.
Section snippets
Animals
For the present study, we used 4 male APPswe/PS1dE9 (APP/PS1) transgenic mice (tg) and 3 age-matched WT littermates (all animals underwent the full experiment). The APP/PS1 founder mice were originally obtained from John Hopkins University, Baltimore, MD, USA (D. Borchelt and J. Jankowsky, Department of Pathology) and a colony was first established at the University of Kuopio, Finland. Thereafter, a colony was bred at the Central Animal Facility at Radboud University Medical Center, the
Increased LFP power in 6–26 Hz band in APP/PS1 mice
We recorded both LFP and single-cell activity with a 128-channel silicon probe in the frontal cortex of 9-month-old awake, head-fixed APP/PS1 mice, and WT littermate controls (Fig. 1). We found increased theta and beta LFP power between 6 and 26 Hz in the frontal cortex neurons of APP/PS1 mice (saline injected APP/PS1 n = 4 mice, 6 sessions; saline injected WT n = 3 mice, 4 sessions; permutation test at each frequency p < 0.05) (Fig. 2).
Reduced single-cell firing rates in the frontal cortex of APP/PS1 mice
To test how increased LFP power in the theta and beta
Discussion
Amyloid pathology has been shown to influence the balance between inhibition and excitation at the level of individual cells and synapses in vitro by modulating both glutamatergic as well as GABAergic neurotransmission at different stages during disease progression (Busche et al., 2012; Minkeviciene et al., 2009; Palop et al., 2007; Zott et al., 2019). Similarly, at the network level, the power of cortical LFP oscillations has previously been reported to be increased in mouse models of AD and
Disclosure statement
The authors report no conflicts of interest.
CRediT authorship contribution statement
Jan L. Klee: Conceptualization, Methodology, Formal analysis, Investigation, Writing - original draft, Writing - review & editing, Visualization, Project administration. Amanda J. Kiliaan: Conceptualization, Resources, Writing - original draft, Writing - review & editing. Arto Lipponen: Conceptualization, Methodology, Investigation, Writing - original draft, Writing - review & editing, Visualization, Supervision, Funding acquisition, Project administration. Francesco P. Battaglia:
Acknowledgements
The authors thank Prof. Heikki Tanila for helpful comments on the manuscript and Jos Dederen and Vivienne Verweij for excellent technical support. The study was supported by the Säätiöiden post doc -pooli (The Finnish Cultural Foundation) to Dr. Arto Lipponen. Silicon probes were manufactured by IMEC (Leuven, Belgium) with funding from the European Union's Seventh Framework Program (FP7/2007–2013) under grant agreement nr. 600925 (NeuroSeeker).
The article meets the guidelines for ethical
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