Abstract
Accumulating evidence suggests that schizophrenia is a disorder of the brain’s communication, a result of functional and structural dysconnectivities. Patients with schizophrenia exhibit irregular neuronal circuit and network activity, but the causes and consequences of such activity remain largely unknown. Inhibition of 14-3-3 proteins in the mouse brain leads to the expression of multiple schizophrenia endophenotypes. Here we investigated how 14-3-3 inhibition alters neuronal network activity in the mouse hippocampus (HPC) and prefrontal cortex (PFC), key brain regions implicated in schizophrenia pathophysiology. We implanted monopolar recording electrodes in these two regions to record local field potentials both at rest and during a cognitive task. Through our assessment of band power, coherence, and phase-amplitude coupling, we found that neural oscillations in the theta and gamma frequency ranges were altered as a result of 14-3-3 dysfunction. Utilizing transgenic and viral mouse models to assess the effects of chronic and acute 14-3-3 inhibition on oscillatory activities, respectively, we observed several fundamental similarities and differences between the two models. We localized viral mediated 14-3-3 protein inhibition to either the HPC or PFC, allowing us to assess the individual contributions of each region to the observed changes in neural oscillations. These findings identify a novel role of 14-3-3 proteins in neural oscillations that may have implications for our understanding of schizophrenia neurobiology.
Highlights
Schizophrenia is a chronic and disabling psychiatric disorder that affects approximately 3 million Americans, and the economic burden of schizophrenia is tremendous (Cloutier et al, 2016)
We previously reported that our function knockout (FKO) mice, with high difopein transgene expression in the prefrontal cortex (PFC) and hippocampus (HPC), displayed behavioral and cognitive deficits that correspond to core schizophrenia endophenotypes
As phase-amplitude coupling of theta and gamma oscillations is recognized as an important modulator of memory and cognition (Tort et al, 2008, 2009; Lisman and Jensen, 2013; Colgin, 2015; Tamura et al, 2017; Nandi et al, 2019), and dysfunction in the neural circuits supporting this coupling in schizophrenia may be responsible for the disordered thoughts and deficits in learning and memory observed in patients, we used the modulation index to measure both local and inter-regional theta-gamma coupling (Moran and Hong, 2011; Mathalon and Sohal, 2015; Barr et al, 2017; Nandi et al, 2019)
Summary
Schizophrenia is a chronic and disabling psychiatric disorder that affects approximately 3 million Americans, and the economic burden of schizophrenia is tremendous (Cloutier et al, 2016). 14-3-3 Inhibition Alters Neural Oscillations of schizophrenia (Foote et al, 2015) These FKO mice transgenically express yellow fluorescent protein (YFP)-fused difopein (dimeric-fourteen-three-three peptide inhibitor) to disrupt the endogenous functions of 14-3-3 proteins in the brain using a neuronal-specific Thy-1 promoter. 14-3-3 proteins exist as homo- and heterodimers, with each monomer made up of nine antiparallel α-helices that form an amphipathic groove for binding ligands with phosphoserine/phosphothreonine motifs (Fu et al, 2000). They are known to interact with hundreds of proteins to regulate diverse neurobiological processes including neuronal development, apoptosis, and synaptic transmission (Skoulakis and Davis, 1998; Zhang and Zhou, 2018). They are known to interact with hundreds of proteins to regulate diverse neurobiological processes including neuronal development, apoptosis, and synaptic transmission (Skoulakis and Davis, 1998; Zhang and Zhou, 2018). 14-3-3 protein dysfunction has been implicated in a number of neurological diseases such as Parkinson’s disease, Alzheimer’s disease, bipolar disorder, and schizophrenia (Foote and Zhou, 2012; Kaplan et al, 2017; McFerrin et al, 2017; Fan et al, 2019; Gu et al, 2020)
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