Disorganization of Oscillatory Activity in Animal Models of Schizophrenia

Abstract

Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganized cognition and behavior. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. In this article, we review the potential role of oscillatory circuits in the disorder with a particular focus on the hippocampus, a region that encodes sequential information across time and space, as well as the frontal cortex. Several mechanistic explanations of schizophrenia propose that a loss of oscillatory synchrony between and within these brain regions may underlie some of the symptoms of the disorder. We describe how these oscillations are affected in several animal models of schizophrenia, including models of genetic risk, maternal immune activation (MIA) models, and models of NMDA receptor hypofunction. We then critically discuss the evidence for disorganized oscillatory activity in these models, with a focus on gamma, sharp wave ripple, and theta activity, including the role of cross-frequency coupling as a synchronizing mechanism. Finally, we focus on phase precession, which is an oscillatory phenomenon whereby individual hippocampal place cells systematically advance their firing phase against the background theta oscillation. Phase precession is important because it allows sequential experience to be compressed into a single 120 ms theta cycle (known as a ‘theta sequence’). This time window is appropriate for the induction of synaptic plasticity. We describe how disruption of phase precession could disorganize sequential processing, and thereby disrupt the ordered storage of information. A similar dysfunction in schizophrenia may contribute to cognitive symptoms, including deficits in episodic memory, working memory, and future planning.

Maternal immune activation-induced proBDNF-mediated neural information processing dysfunction at hippocampal CA3-CA1 synapses associated with memory deficits in offspring

“…Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons, thereby regulating the likelihood that APs in presynaptic neurons lead to APs in postsynaptic neurons (Kallupi et al, 2014). Consistently, our results showed that the amplitude of EPSCs in the CA1 region declined in MIA offspring, suggesting the disruption of postsynaptic information processing (An and Sun, 2017b;Speers and Bilkey, 2021). It has been demonstrated that NMDARdependent intrinsic excitability in CA1 pyramidal neurons from MIA offspring was markedly reduced, which caused the detrimental effect on spatial memory impairments (Escobar et al, 2011;Zeraati et al, 2021).…”

Large-scale coupling of prefrontal activity patterns as a mechanism for cognitive control in health and disease: evidence from rodent models

“…Therefore, it is not surprising that animal models of SZ displays aberrant oscillatory activity in the PFC (Uhlhaas and Singer, 2010;Senkowski and Gallinat, 2015;Hunt et al, 2017). Several of these prefrontal oscillatory alterations observed in SZ patients have been also found in animal models of SZ (Speers and Bilkey, 2021). For example, it have been observed decreased prefrontal gamma oscillations in models of impaired E/I balance (Pinault, 2008;Ahnaou et al, 2017;Ma et al, 2018), in the MAM neurodevelopmental model and the genetic models as Dlx5/6 +/− , DISC1-mutant mice and Arc/Arg3.1 deficient mice (Cho et al, 2015;Gao et al, 2019;Sauer and Bartos, 2022).…”

“…The combination of these hypotheses into an integrative vulnerability-stress model (known as a “two-hit model”), which combines genetic with pre- and postnatal environmental factors, has become one of the most accepted postulates for the development of SZ, which also reveals the complexity and interaction of several factors in its physiopathology ( Bayer et al, 1999 ; Davis et al, 2016 ). Thus, considering these hypotheses, together with the most relevant factors for the development of SZ, several rodent models have been developed ( Table 1 ), in which cognitive impairments are usually evident ( Lipska and Weinberger, 2000 ; Marcotte et al, 2001 ; Jones et al, 2011 ; Winship et al, 2019 ; Speers and Bilkey, 2021 ). For example, neurodevelopmental models, such as prenatal administration of methylazomethanol (MAM) ( Lodge and Grace, 2009 ) display impairments in several cognitive functions, including cognitive control ( Kállai et al, 2020 ).…”

Editorial: In vivo investigations on neurological disorders: From traditional approaches to forefront technologies

“…Electroencephalography (EEG) monitors electrical brain activity in sleepy or awake animals. Analysis of the waveforms can increase knowledge about brain functionality, providing suitable electrical biomarkers to detect a disorder or to follow its progression (Levenstein et al, 2017 ; Trenado et al, 2019 ; Girardeau and Lopes-dos-Santos, 2021 ; Speers and Bilkey, 2021 ).…”