Translating the MAM model of psychosis to humans

Abstract

Elevated dopamine function and alterations in the medial temporal lobe structure and function (MTL) are two of the most robust findings in schizophrenia, but how interactions between these abnormalities underlie the onset of psychosis is unclear. Although several preclinical models of psychosis have been proposed, the methylazoxymethanol acetate (MAM) rodent model provides a mechanistic account linking these two clinical observations. The model proposes that psychosis develops as a result of a perturbation of MTL function, leading to elevated striatal dopamine dysfunction. We review a number of recent neuroimaging studies that examine components of the putative model in people with an ultra high risk (UHR) of psychosis. Whilst data from these studies are broadly consistent with the MAM model, that the potential for comparing various kinds of neurobiological data across animal and human studies imposes some limitations on what can be inferred from these data. Going forward, longitudinal studies are needed to explicitly test the model’s predictions in UHR populations.

Using neuroimaging to help predict the onset of psychosis

“…The integration of data from different modalities may be particularly useful in predicting the onset of psychosis, as it is the result of interactions between a diversity of genetic, environmental and neurobiological factors 87 . Moreover, multimodal neuroimaging studies in UHR subjects indicate that the normal relationships between glutamate and grey matter volume (MRS and sMRI) 88 , glutamate and functional activity (MRS and fMRI) 89 90 91 , glutamate and dopamine (MRS and PET) 92 and dopamine and functional activity (PET and fMRI) 15 93 are perturbed.…”

Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model

“…Therefore, one can glean from human imaging and pharmacological studies which systems seem to have a primary involvement in the disorder (e.g., hippocampus, prefrontal cortex, dopamine), and examine in animals how these systems function in the normal state (Modinos et al, 2015). We can also incorporate information regarding genetic and environmental risk factors into rodent models to examine how these can negatively impact the normal balance present in these systems.…”

“…Several developmental disruption models have been advanced, including early life immune activation, neonatal ventral hippocampal lesions, and the MAM model; nonetheless, despite the multifaceted mechanisms used by such interventions, the adult animal pathophysiology is remarkably similar in nature (Meyer and Feldon, 2009; Modinos et al, 2015; Tseng et al, 2009). Importantly, this is consistent with the concept that schizophrenia is a disorder with multiple etiologies.…”

MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function

“…The symptoms of schizophrenia become most prominent post-puberty and are linked to disruption of cortical circuitry including a decrease in GABAergic interneuron function (Hashimoto et al 2003;Hoftman et al 2015;Torrey et al 2005) and dysregulation of the mesolimbic DA system (Howes and Kapur 2009). The MAM E17 rodent model has been shown to capture each of these aspects of the hypothesized neurobiology of the disease (Lodge et al 2009;Lodge and Grace 2007Modinos et al 2014;Moore et al 2006). In the present studies, we sought to characterize behavioral and cognitive functions in the MAM model to see how well group differences in MAM task performance overlap with the cognitive and behavioral symptoms of schizophrenia.…”

“…Efforts to pinpoint how dysregulation of these two systems contributes to the disorder have been limited by a lack of animal models that capture both major facets. Administration of the DNA-alkylating agent methylazoxymethanol (MAM) in rodents on embryonic day 17 (E17) has been suggested to reproduce structural, neurochemical, neurophysiological, and cognitive aberrations associated with schizophrenia (Lodge and Grace 2007;Modinos et al 2014;Moore et al 2006), including impairments in sensory gating, a sensitized behavioral and neurochemical response to pharmacologically induced elevations in striatal dopaminergic tone, and altered prefrontal physiology including a reduction in parvalbumin positive interneurons (Ewing and Grace 2013;Flagstad et al 2004;Le Pen et al 2006;Lodge et al 2009;Grace 2007, 2008;Ratajczak et al 2013). These reductions in cortical parvalbumin expression have importantly been linked to disrupted ventral hippocampal control of ventral striatal activity in the MAM model (Lodge et al 2009;Lodge and Grace 2008).…”