Animal Models of Developmental Neuropathology in Schizophrenia
Year: 2017
Type: article
Abstract: Schizophrenia is a heterogenous psychotic disorder of undetermined etiologies for which available treatments are limited. Recent advances in appreciating both genetic and environmental influences on risk for this disorder have raised tremendous hope for identifying actionable risk factors and correctable neuropathological processes. However, the development of preventive or therapeutic interventions requires model systems through which molecular hypotheses can be tested. This commentary is not intended as a broad consideration of the use of animal models in psychosis research, several of which have been published recently.1–3 Rather, we focus on a few examples that highlight how recent genetic and environmental advances, together with advances such as stem cell derived neural cells and the study of circuitry function in vivo, are shaping the use of animal models. A useful way to consider animal models of human disorders is based on their validity. This can include construct validity, how well the model recapitulates a known or postulated etiologic process, and face validity, how well the model recapitulates symptom features.4 To be useful, a model with high construct validity need not closely recapitulate a disorder’s symptoms, if it sheds light, eg, on the molecular or circuit neurobiology of a developmental process that appears to go awry in the disorder. Such light could be crucial for developing predictive tests leading to intervention that redirects neurodevelopment back onto a normative trajectory prior to symptom onset. On the other hand, a model with high face validity need not closely recapitulate the initial etiological components of a disorder, if it recapitulates symptoms in a manner that could be useful for novel treatment discovery. This issue with face validity may be particularly important for treatment development in schizophrenia, where variations at more than a hundred risk-imparting genetic loci, interacting with each other and with environmental influences, ultimately converge in the pathophysiology of symptoms. Here, we focus on two rodent models, the 22q11 deletion syndrome (22q11DS) and ventral hippocampal hyperactivity. The former has excellent construct validity, but is less useful as a model of psychosis-related symptoms. The later has excellent face validity but is less useful as a model of neurodevelopmental conditions leading to those symptoms. Despite their limitations, studies using multimodal approaches with these models are shedding important light on risk, resilience, and novel treatments for schizophrenia. We will then discuss the burgeoning use of marmosets in schizophrenia research, a phenomenon that may bring the convergence of animal model construct and face validity to an entirely new level. The 22q11DS is a hemizygous deletion of 1.5–3.0 MB on chromosome 22q11.2 that appears be the strongest genetic risk factor for schizophrenia.5,6 An estimated 25% of patients with 22q11DS develop schizophrenia, with age of onset and symptom spectrum that is typical of this disorder.7,8 However, the sex differences favoring increased rates of schizophrenia in younger adult males is not seen in 22q11DS.9 In addition to schizophrenia, 22q11DS is associated with autism spectrum disorders, intellectual disability, attention deficit hyperactivity disorder, anxiety, and depression,9 as well as craniofacial abnormalities and multiple somatic comorbidities including cardiac, gastrointestinal, and immune dysregulation.10 Despite the symptom complexity and variability associated with 22q11DS, the fact that almost one-third of these patients develop schizophrenia by young adulthood has generated tremendous interest in developing mouse models.11 The identification of a largely syntenic region to Chr2211.2 on mouse chromosome 16, combined with the application of Cre-lox technology for the creation of large deletions, led to the creation of a handful of mouse 22q11DS models and several dozen publications (for examples of the deletions of the entire syntenic region on mouse Chr16, directly affecting 27 genes homologous to those deleted in the 1.5 MB minimum critical deleted region in 22q11DS see12–14). While these models and others harboring smaller or single deletions present a variety of structural, functional, and behavioral deficits relevant to a range of neuropsychiatric disorders,11 a comprehensive discussion of their phenotypes is beyond the scope of this review. Here, we will briefly focus on circuitry analyses in the hippocampus and medial frontal cortex in relation to schizophrenia-related cognitive deficits. Multiple lines of evidence have suggested that schizophrenia can involve disruption in interareal cortical connectivity, particularly that of the hippocampus and prefrontal cortex (PFC).15 Optogenetic and other in vivo analyses of circuitry function in rodents are accelerating the understanding of how hippocampal-cortical connectivity mediates aspects of spatial and social working memory.16–18 In the 22q11DS model, this technology has recently been applied with remarkable success at finding abnormalities in circuitry that influence the oscillations of PFC ensembles, as well as working memory, a major deficit area in patients with schizophrenia.19–21 Even more importantly, the model has been used to successfully demonstrate that both hippocampal-PFC connectivity and spatial working memory can be normalized by administration of an inhibitor of Gsk322. With the advances in gene editing, future studies are likely to include polygenic mouse mutants that allow for the identification of which combinations of gene deletions within the 22q11.2 syntenic region recapitulate the above phenotypes. In addition, despite the variable penetrance of neuropsychiatric phenotypes in 22q11DS, to date there has been little effort in the mouse models to link cognitive performance to circuitry disruption at the individual level. In both genetically undefined schizophrenia and in that associated with 22q11DS, cognitive impairment typically precedes the onset of psychosis.23,24 Thus, connecting cognitive impairment to physiological impairment in individual mice could allow for the identification of additional factors influencing risk and resilience to these impairments. Such factors could include genetic, placental, microbiome, immunological, and sleep patterns, and also include environmental manipulations (ie, pre- and postnatal stress, cannabis) that, identified by extensive screening in mice, may be used to develop biomarkers for assessing risk and resilience in children with 22q11DS. Finally, while 22q11DS mouse models have been tremendously successful in linking construct validity (the similarity of the mouse model with human deletion) with face validity (disconnectivity and working memory deficits), these models have been less useful in modeling positive symptom-like behaviors, which are generally associated with increased striatal dopamine. The next section explores a different model with low construct validity but with strong face validity related to both positive and negative symptoms. Genetic studies of schizophrenia have implicated over 100 loci wherein variants can increase risk.25 Analyses of many of these genes, together with clinical and preclinical studies, suggest that the symptomatology of schizophrenia is often produced by pathophysiologies that are well downstream of the incipient developmental pathology. This situation suggests that while studies of genetic and early developmental causes of schizophrenia may lead to novel approaches for risk detection and primary prevention, treatments for schizophrenia patients will target pathophysiological mechanisms that more directly underlie psychopathology rather than the incipient cause. A promising location for such treatment targeting is the hippocampus, wherein excess metabolic activity strongly correlates with psychosis and cognitive deficits in patients with schizophrenia.26–29 In support of this imaging data, postmortem data show reductions of inhibitory interneurons in the ventral hippocampi of some patients with schizophrenia.30 In a remarkable example of using animal models to develop the rationale for a spatially targeted treatment in schizophrenia, two groups using different models and rodent species have demonstrated that embryonic disruptions leading to hippocampal hyperactivation, and the psychosis-related behaviors associated with it, can be reversed in adults by transplantation of GABAergic interneurons into the hippocampus. The first group used a toxicity model, wherein prenatal administration of methylazoxymethanol acetate (MAM) results in a variety of histological, electrophysiological, and behavioral phenotypes that resemble some aspects of schizophrenia psychopathology.31,32 These aspects include reduced hippocampal expression of the GABAergic interneuron subgroup marker parvalbumin, increased hippocampal activity, and abnormalities in tasks involving hippocampal-prefrontal cortical connectivity, including reversal learning. They also include increased striatal dopamine (DA) and hyperambulation to amphetamine challenge, secondary to increased tonic firing of midbrain dopaminergic neurons. Interestingly, many of these phenotypes can be reversed in adults by focal, graded inhibition of hippocampal activity, either by pharmacological or deep brain stimulation approaches,33,34 or hippocampal transplantation of the embryonic precursors of cortical inhibitory interneurons.35 Recently, this transplantation approach was further developed to employ embryonic stem cell–derived cortical interneuron-like cells, in pools enriched for either parvalbumin (PV; fast-spiking, soma and proximal dendrite targeting) or somatostatin (SST; burst or regular spiking, distal dendrite targeting)—expressing subclasses.36,37 Both subgroup transplants normalized the hippocampal hyperactivity, the tonic firing of midbrain DA neurons, hyperambulation to amphetamine, and reversal learning. However, only the PV subclass-enriched transplants normalized deficits in extradimensional set shifting. Remarkably, the authors also showed that optogenetic silencing of the transplanted interneurons in the hippocampus immediately reversed their normalization of midbrain DA neuron tonic firing, firmly establishing that the transplants are directly influencing synaptic transmission and hippocampal output. This selectivity could form the basis of future studies designed to determine how the transplants affect hippocampal circuitry, and why the interneuron subclasses differentially influence psychosis-related cognitive deficits, a platform from which novel therapeutic interventions could be generated. Finally, a second group found very similar effects on hippocampal hyperactivity and psychosis-related behaviors from interneuron precursor transplants into transgenic mice lacking cyclin D2 (CCND2).38 Like the MAM model, these mice have a variety of brain abnormalities, some of which resemble schizophrenia-related phenotypes such a decrease in PV-expressing interneurons in the hippocampus,39 and some of which do not such as microcephaly and loss of adult hippocampal neurogenesis. The PV phenotype appears to be secondary to reduced embryonic generation of this interneuron subclass.39,40 Consistent with the reduction in hippocampal PV interneurons, cyclin D2 nulls have hippocampal hyperactivity, increased hippocampal blood flow (by PET), increased tonic firing of midbrain DA neurons, hyperambulation to amphetamine, and cognitive impairment as measured by contextual fear conditioning.38,39 Transplants of mixed pools of PV and SST interneuron precursors from embryonic mouse brains into the hippocampus of adult cyclin D2 mice corrected all of the above phenotypes, including the enhanced hippocampal blood flow.38 Here, we have two rodent models featuring disruption of embryonic development. One model is environmental and one genetic, and both cause various phenotypes unrelated to psychosis, but both feature reduced PV expression in the hippocampus, hippocampal hyperactivity, midbrain, and striatal DA neuron abnormalities, and a variety of psychosis-related behavioral phenotypes. In adults of both models, interneuron transplants normalize the hippocampal hyperactivity and downstream phenotypes. These findings strongly support the contention that independent of the incipient pathology, for those patients with prodromal or actual schizophrenia and who also have hippocampal hyperactivity, treatment targeting this activity with graded enhancement of inhibition may be highly therapeutic. Recent combination of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) with an interneuron-selective enhancer to affect adult cortical interneuron function after focal AAV administration41 may be one of multiple novel approaches for the focal application of graded effectors of cell-type-specific activity to create novel treatments for schizophrenia. While rodent models of schizophrenia remain a useful choice for many studies, the common marmoset has emerged as a promising model for the integration of both construct and face validity through genetic, behavioral, functional circuitry, and histological analyses. The PFC controls cognitive and executive functions disrupted in schizophrenia, but there are major structural and functional differences between the PFC in human and the medial frontal cortex in rodents.42,43 As a primate, the marmoset PFC closely resembles the human in anatomy and function,44 including the periadolescent pruning of frontal cortical dendritic spines.45 Moreover, marmosets are easily bred in captivity, maintain complex social behaviors, and their relatively small brain and lissencephalic neocortex facilitate the focal application of optogenetic and pharmacogenetic manipulations.46 Tests for cognitive flexibility, working memory, fear generalization, negative bias, and anhedonia have also been developed in the marmoset.47 With development of transgenic marmosets,46 it appears likely that a new generation of animal models for aspects of schizophrenia-related pathology, featuring the integration of vastly improved levels of construct and face validity, will soon engender discoveries leading to novel prevention and treatment strategies.
Source: Schizophrenia Bulletin
Authors: Nickole Kanyuch, Stewart Anderson
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2755342201