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Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap

Key Points

  • Schizophrenia is a common and extremely debilitating neuropsychiatric disease, yet — arguably — the search for improved treatments has not advanced substantially over the past 20 years.

  • This lack of success may reflect the widespread use of simple assays for drug testing (with their seductively high throughput) in oversimplistic models of the disease.

  • The knowledge of the genetic and environmental causes of schizophrenia has advanced substantially in recent years, as has our ability to detect altered aspects of rodent behaviour that share features with those that are characteristic of the human disease as well as the neural systems that underpin these shared features.

  • In this Review, we advocate that the use of disease models that are based on disease mechanisms — in conjunction with assay systems with end points that can be translated directly into the clinic — will accelerate the drug discovery process.

  • Close integration of preclinical and clinical programmes is essential for translational neuroscience strategies to be successful.

Abstract

Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process.

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Figure 1: Genes implicated in schizophrenia converging at the synapse and nucleus.
Figure 2: Dysfunctional connectivity in schizophrenia.

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Glossary

Avolition

Generalized lack of motivation to perform tasks or undertake activities: probably linked to other negative symptoms such as social withdrawal and anhedonia (inability to take pleasure in activities).

Reduced affect

Loss of emotional responsiveness (for example, when talking); characteristic of schizophrenia and major depressive disorder.

Construct validity

An animal model has construct validity when the experimental mechanisms used to create the model are related to the underlying mechanisms involved in disease aetiology.

Pyramidal cell

A large neuron with a cell body roughly in the shape of a pyramid. These neurons use glutamate as their transmitter, and in many cases send fibres for considerably long distances to stimulate neurons in other parts of the brain.

Prepulse inhibition

(PPI). A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in PPI have been observed in patients with schizophrenia as well as in patients with other psychiatric and neurological disorders.

Predictive validity

An animal model has predictive validity when predictions (for example, of drug efficacy) made using the model are informative for when an equivalent drug is used clinically in patients.

Attentional set-shifting task

A task that is used for assessing rule learning and cognitive flexibility in rodents. Animals learn a set of stimulus–reward associations (for example, a particular odour associated with food reward) while simultaneously ignoring another stimulus (for example, texture). The rules are then changed such that texture is the salient stimulus.

Intradimensional–extradimensional shift

A test of rule acquisition and reversal that is sensitive to frontostriatal regions.

Continuous performance task

A task that measures the ability of a subject to maintain sustained and selective attention and inhibitory control.

Radial arm maze

Usually an eight-armed maze that can be used for various memory tasks. In the context of working memory, a rodent explores the eight arms in search of food. Working memory can be assessed by measuring how often the animal returns to an arm that it has already visited and emptied of food reward.

n-back task

The subject is presented with a series of stimuli and is required to respond when the stimulus on the current trial matches that presented n trials ago. The memory load can be increased by increasing n. The subject has a dual task: to encode the current stimulus and to compare it with that presented on the n-to-last trial.

Sensorimotor gating

A process of filtering redundant or unnecessary stimuli in the brain.

Face validity

An animal model or assay in which the outward signs resemble the human condition but may not necessarily be a result of the same underlying mechanism.

Operant assays

Tasks in which the subject learns to behave in such a way to obtain rewards or avoid punishments.

Parvalbumin

A calcium-binding protein expressed in a subset of GABA (γ-aminobutyric acid)-ergic cells, including cortical and hippocampal basket and chandelier cells as well as reticular thalamic neurons. Levels of parvalbumin in some areas of the cortex and hippocampus are reduced in post-mortem tissue samples taken from patients with schizophrenia.

γ-oscillations

Oscillatory waves detected in human electroencephalography, with a frequency typically around 40 Hz; thought to be related to consciousness.

Basket cells

A class of GABA (γ-aminobutyric acid)-ergic inhibitory interneurons that innervate the perisomatic region of target neurons. The axonal arborization of basket cells often resembles a basket surrounding the target cell body.

Chandelier cells

A class of GABA (γ-aminobutyric acid)-ergic interneurons of the cerebral cortex that ensheathe the axon initial segment of up to 200 pyramidal cells with cartridge synapses to directly control action potential generation.

Working memory

The active maintenance of limited amounts of information for a short period of time to guide thought processes or sequences of behaviour.

High penetrance

A genetic mutation that has a substantial influence on the risk of disease.

Deep re-sequencing

A technique, typically performed using high-throughput next-generation sequencing, used to obtain the complete nucleotide sequence of a gene or genome that has previously been determined. The term 'deep' refers to the depth, coverage or the number of times an individual nucleotide is sequenced.

Global mining

Non-hypothesis-driven screening of an entire set of biological material, such as the use of microarrays to screen all the RNA from a particular cell type.

22q11 syntenic region

Synteny describes the preservation of colocalized genes on chromosomes in different species. Mouse genes that are orthologous to the human genes that map onto human chromosome 22q11 are grouped together on mouse chromosome 16.

Progressive ratio schedule

A schedule in which the number of responses a subject is required to make to obtain a reinforcement (such as a food reward) increases progressively. A typical performance measures the ratio at which responding ceases for a predefined period, which may be related to the subject's motivational state.

Human constructs

In relation to cognition, human constructs are specific elements of mental processes, such as attention, memory, producing and understanding language, solving problems and making decisions.

Reference memory

Also known as long-term memory. In rodents this typically involves reference to external cues, which is needed for succesful completion of tasks such as finding a hidden platform in the Morris water maze.

L100P mutation

A genetic modification induced by N-ethyl N-nitrosourea mutagenesis in the mouse disrupted in schizophrenia 1 (Disc1) gene, whereby an adenine to thymine nucleotide transition causes the amino acid at position 100 of the DISC1 peptide to change from a leucine to a proline.

Q31L mutation

A genetic modification induced by N-ethyl N-nitrosourea mutagenesis in the mouse disrupted in schizophrenia 1 (Disc1) gene, whereby a thymine to cytosine nucleotide transition causes the amino acid at position 31 of the DISC1 peptide to change from a glutamine to a leucine.

Partial least squares regression

A multivariate modelling method that is useful for quantitatively defining the relationship between several collinear predictors and response variables. In neuroimaging it has been used to define functional connectivity between regions of the brain.

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Pratt, J., Winchester, C., Dawson, N. et al. Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. Nat Rev Drug Discov 11, 560–579 (2012). https://doi.org/10.1038/nrd3649

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