Elsevier

Experimental Neurology

Volume 344, October 2021, 113805
Experimental Neurology

Research paper
Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice

https://doi.org/10.1016/j.expneurol.2021.113805Get rights and content

Highlights

  • Compulsive-like behavior, but not anxiety-like behavior, is exhibited by 3–5-month-old APP/PS1 mice.

  • Altered oscillations and PV interneuron-mediated SPN firing occur in Str of APP/PS1 mice.

  • Abnormal synchronization between PFC and Str occurs in APP/PS1 mice.

  • Downregulation of GABAB receptors is associated with neural changes in the corticostriatal circuit of APP/PS1 mice.

Abstract

Mild behavioral impairment (MBI), which can include compulsive behavior, is an early sign of Alzheimer's disease (AD), but its underlying neural mechanisms remain unclear. Here, we show that 3–5-month-old APP/PS1 mice display obsessive-compulsive disorder (OCD)-like behavior. The number of parvalbumin-positive (PV) interneurons and level of high gamma (γhigh) oscillation are significantly decreased in the striatum of AD mice. This is accompanied by enhanced β-γhigh coupling and firing rates of putative striatal projection neurons (SPNs), indicating decorrelation between PV interneurons and SPNs. Local field potentials (LFPs) simultaneously recorded in prefrontal cortex (PFC) and striatum (Str) demonstrate a decrease in γhigh-band coherent activity and spike-field coherence in corticostriatal circuits of APP/PS1 mice. Furthermore, levels of GABAB receptor (GABABR), but not GABAA receptor (GABAAR), and glutamatergic receptors, were markedly reduced, in line with presymptomatic AD-related behavioral changes. These findings suggest that MBI occurs as early as 3–5 months in APP/PS1 mice and that altered corticostriatal synchronization may play a role in mediating the behavioral phenotypes observed.

Introduction

Alzheimer's disease (AD) patients can develop neuropsychiatric symptoms, such as apathy, changes in response control and emotional dysregulation (Fernández-Martínez et al., 2008; Goukasian et al., 2019; Marchant et al., 2020; Nancy J. Donovan et al., 2018). There is increasing evidence that the mild behavioral impairment (MBI) observed before the onset of cognitive decline may be an early sign of AD. Recent studies have shown that obsessive-compulsive disorder (OCD), which involves obsessive thoughts and compulsive behavior, might be a characteristic of the early stages of AD (Dondu et al., 2015; Moheb et al., 2019). In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), OCD has been reclassified in a new category of neuropsychiatric disorder and is now known as a transdiagnostic psychiatric trait (Gillan et al., 2016). However, the molecular mechanisms and neural circuits by which mild changes in behavior during presymptomatic AD are mediated remain unclear.

Mounting evidence supports the notion that changes in corticostriatal circuits underlie MBI, typified by changes in emotional and compulsive behavior, which can arise in presymptomatic AD (Abbott et al., 2017; Bentea et al., 2020; Burguière et al., 2015; Manning et al., 2015). The striatum (Str) receives strong inputs from the prefrontal cortex (PFC) as part of the process of integrating cognitive information (Lago et al., 2017; Voorn et al., 2004). Studies in rodents suggest that the role played by Str in regulating aberrant behavior is probably executed in combination with other cortical regions, including PFC and its subregions (Fuccillo, 2016; Martos et al., 2017; Yang et al., 2021). OCD is considered to be a common form of MBI, which is controlled by the interconnectivity between PFC and Str (Anticevic et al., 2014; Harvey et al., 2001; Thompson et al., 2019). For example, Sapap3-mutant mice, a mouse model of OCD, have corticostriatal synaptic defects and also exhibit increased anxiety and compulsive grooming behavior (Welch et al., 2007). Loss of Slitrk5 also results in OCD-like behavior and impaired corticostriatal neurotransmission (Shmelkov et al., 2010). Furthermore, PFC and Str are the first regions of the brain to be affected by amyloid deposition (Lo et al., 2013; Ren et al., 2016), and corticostriatal dysfunction might be relevant to AD-related neurodegeneration. Nevertheless, the molecular mechanisms underlying these symptoms of MBI during presymptomatic AD are not clear.

The oscillatory neural network is linked to multiple types of behavior and performance of cognitive tasks, while regulation of GABA transmission and GABA interneuron excitability is impaired in AD models (Bi et al., 2020; Zhong et al., 2003). Oscillations in the gamma (γ) range are abnormal in a mouse model of AD due to compromised synaptic activity (Etter et al., 2019). Meanwhile, GABAergic inhibition, which modulates oscillatory activity in the γ range (30–100 Hz), can modify symptoms of MBI and affect the excitation-inhibition balance (Egashira et al., 2013; Luo et al., 2020; Sun et al., 2019; Xu et al., 2019). Considering these previous findings, it is of interest to explore whether and how the GABAergic system in corticostriatal circuits modulates aberrant behavior in presymptomatic AD.

In the present study, we evaluated the interconnection of PFC-Str inputs at the cellular and molecular levels in 3–5-month-old APP/PS1 mice with symptoms of MBI. We found distinct changes in striatal oscillations in the beta (β) and high γ (γhigh) ranges, as well as altered synchronization in corticostriatal circuits. Consistent with their aberrant γ rhythms, APP/PS1 mice show increased striatal neuronal activity, decreased numbers of neighboring parvalbumin (PV)-interneurons and reduced GABAergic inhibition, suggesting that molecular changes in corticostriatal circuits mediate aberrant behavior during presymptomatic AD.

Section snippets

Animals

APPswe/PSEN1ΔE9 (APP/PS1) transgenic mice and their wild-type (WT) littermates were obtained from Model Animal Research Center of Nanjing University (Nanjing, China). Regardless of sex, 3–5-month-old APP/PS1 mice and WT littermates were used in this study and housed individually in accordance with the guidelines of the National Institutes of Health on animal care and the ethical guidelines of the Ethics Committee for Animal Research at South China Normal University as follows. Mice were housed

Aberrant behavior in 3–5-month-old APP/PS1 mice

It has previously been shown that MBI is an early marker of AD, occurring before cognitive decline and dementia in individuals with normal cognition, and is associated with higher risk of AD in the later-life (Ismail et al., 2017). MBI includes behavioral problems that persist for at least 6 months, such as emotional dysregulation and dyscontrol (Creese et al., 2019). Here, we tested the hypothesis that abnormal behavior occurs in 3–5-month-old APP/PS1 mice. Burying marbles, nestlet shredding

Discussion

Failure to cope with stress or conflict in daily life is associated with abnormal repetitive behavior, which are typical symptoms of MBI (Dillon et al., 2013). Recent studies in rodents report that compulsive behavior is exhibited at different stages of the AD process (Ortega-Martinez et al., 2019; Shepherd et al., 2021). In the present study, we demonstrate compulsive behavior in 3–5-month-old APP/PS1 mice, prior to the onset of disease symptoms in this AD model mouse strain, as evidenced by

Conflict of interests

The authors declare that there are no competing financial interests.

Author contributions

Yi-gang Peng: Investigation, Formal analysis, Visualization. Ping-jing Cai: Investigation, Visualization. Jian-hang Hu: Investigation, Formal analysis. Jin-xiang Jiang: Software, Formal analysis, Visualization, Writing- Original draft preparation. Jia-jia Zhang: Investigation. Ke-fang Liu: Investigation. Li Yang: Supervision, Project administration, Funding acquisition. Cheng Long: Conceptualization, Supervision, Writing – Review and Editing, Funding acquisition..

Acknowledgements

The present study was supported by grants from the National Natural Science Foundation of China (31771219, 31871170, 31970915), the Natural Science Foundation of Guangdong Province (2021A1515010804), the Guangdong Natural Science Foundation for Major Cultivation Project (2018B030336001) and the Guangdong Grant ‘Key Technologies for Treatment of Brain Disorders' (2018B030332001).

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