Opinion
Special Issue: Neuropsychiatric Disorders
Genetic and cognitive windows into circuit mechanisms of psychiatric disease

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Accumulating evidence indicates substantial etiological and pathophysiological heterogeneity as well as overlap within and across psychiatric disorders. Moreover, it is uncertain at what level, besides gross behavior, mental illnesses can be differentiated. To advance our understanding of psychiatric disease, we advocate a more systematic approach in characterizing a small number of animal models by utilizing unequivocal rare disease mutations and targeted cognitive assessment to identify convergent disease circuits and mechanisms. Based on available data, we discuss the possibility that the temporal dynamics of synaptic plasticity play a central role in disease pathophysiology and that the extent and manner in which they are altered in specific neural circuits determine the exact clinical phenotype of diverse disorders.

Introduction

During his voyages, Charles Darwin meticulously annotated the physical features of organisms he encountered, from the curvature of their beaks to the bifurcations of their horns. When naturalists first set out to classify organisms into related taxa, they did so based on easily observable morphological characteristics. The revolution in molecular genetics, however, later revealed unexpected relationships between species that required established phylogenetic trees to be redrawn [1]. A similar change is eminent in psychiatry where diagnostic labels are currently based on observable behavioral characteristics but new genetic findings appear to be challenging the relationships between established psychiatric disorders.

Beyond classification, a major motivation behind elucidating genetic risk is the potential gain in biological insight necessary for treatment development, but making such a translation is not always straightforward. It may in fact prove more challenging than expected given the great degree of etiological heterogeneity apparently underlying risk for mental illnesses 2, 3, 4, 5, 6, 7, 8, 9, 10. This has directed focus, beyond the genetic level, to the level of neural circuits 11, 12 and the idea that the disturbance of distinct neural circuits may define disorders irrespective of ultimate genetic or environmental causes. Currently, however, given our incomplete understanding of disease pathophysiology, there is no consensus on how best to identify relevant and disease-specific neural circuits.

Here we discuss a research strategy for taking advantage of human genetics to discover pathophysiological circuits and the mechanisms by which they falter in psychiatric disorders. We argue that a promising translation of genetic findings is modeling in animals a few rare but recurrent mutations unequivocally associated with well-defined clinical presentations and utilizing advanced behavioral techniques to identify and characterize disease-relevant circuits. So far, this approach indicates that the temporal dynamics of synaptic plasticity across different brain systems may play a central role in disease pathophysiology. We thus suggest that, although there is overlap of neural circuit dysfunction among psychiatric disorders, within these circuits the exact spatial and temporal scale of structural and functional deficits, respectively, need to be analyzed in a systematic manner to reconcile genetic heterogeneity with etiology and account for the diverse set of symptoms across disorders.

Section snippets

Prominent genetic heterogeneity, promiscuous mutations and functional pathways

Currently there are several approaches to uncovering the genetic architecture of psychiatric disorders, and recent findings point to an unanticipated degree of genetic complexity for diseases such as schizophrenia (SCZ) making this endeavor significantly more challenging (Box 1). Nevertheless, elucidating disease circuits and mechanisms of specific disorders amidst substantial etiological and pathophysiological heterogeneity requires understanding the nature of genetic risk and the

Cognitive tools for identifying neural circuits and mechanism

Carefully characterizing cognitive deficits across psychiatric disorders can provide important clues into their underlying neural basis. Cognitive impairments are found, to varying degrees, in all major neurodevelopmental and psychiatric disorders as well as unaffected relatives 35, 36, 37, and cognition is now a prime target for remediation owing to its central role in determining functional outcome [38]. Indeed, cognitive deficits may be central to many disorders – even those for which

Short-term plasticity and long-range communication as cognitive substrates

As discussed above, the pattern of cognitive deficits in SCZ and related mutant models suggests changes in information processing and not in long-term information storage. Generally, long-term structural and functional plastic changes are thought to form the basis of stored information such as that encoded into episodic memory. On a shorter timescale, neural dynamics and short-term plasticity (STP), fast and transient changes in synaptic efficacy, are more closely related to the

Concluding remarks

The emerging picture from psychiatric genetics is one of substantial mutational heterogeneity within and across disorders. Modeling in animals a few selected mutations with robust disease associations makes gaining insights into mechanisms of disease pathogenesis and pathophysiology possible. Such insights, however, will require systematic and comparable analyses of models from different disorders and disease-associated mutations so as to gain disease-specific understanding (Figure 4).

Based on

Acknowledgments

Work described in this article has been supported by US National Institute of Mental Health grants MH67068, MH077235 and MH080234 and by a grant from the Simons Foundation. We thank Maria Karayiorgou, Amy MacDermott and Gerald Fischbach for useful discussions. We also thank members of the Gogos and Karayiorgou laboratories (especially Bin Xu, Kim Stark, Karine Fenelon and Liam Drew) for their contributions to the work described here and Laura Rodriguez Murillo for help in preparing Figure 1.

Glossary

Cognitive control
the ability to guide behavior flexibly and efficiently based on current goals in the face of interfering or competing demands.
Dysconnectivity
any abnormal (including both increases or decreases) structural or functional connectivity between neurons or brain regions.
Fragile X syndrome
a developmental condition of learning and intellectual disability, often accompanied by autistic-like features, that is caused by transcriptional silencing of the FMR1 gene on the X chromosome.

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