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Interneuron dysfunction in psychiatric disorders

Key Points

  • GABAergic interneurons constitute the main elements that control excitability and shape oscillatory rhythms in the cerebral cortex. Multiple classes of interneuron exist, with similar but slightly divergent developmental trajectories.

  • Disruption of the development or function of GABAergic interneurons in the cerebral cortex leads to epilepsy and may contribute to the emergence of specific symptoms of certain neuropsychiatric disorders, in particular those associated with cognitive impairment.

  • Abnormal development of fast-spiking parvalbumin-expressing interneurons may predispose individuals to schizophrenia. Susceptibility genes for this disorder are thought to have a crucial role in the early development and wiring of this specific interneuron population.

  • In autism spectrum disorders, disruption of the excitatory–inhibitory balance may occur in several neural systems, including the neocortex, the basal ganglia and the hindbrain. It is presently unclear whether such defects are caused by deficits in specific classes of interneuron.

  • Increasing evidence indicates that abnormal GABAergic function is linked to several other neurological conditions, including Angelman's syndrome, fragile X syndrome and neurofibromatosis type I.

Abstract

Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons — the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.

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Figure 1: Cortical interneuron diversity and its developmental origin.
Figure 2: Alterations found in cortical circuits in patients with schizophrenia and in animal models of this disorder.
Figure 3: Genetic dissection of methyl-CpG-binding protein 2 function in the mouse brain.

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Acknowledgements

I would like to thank M. Maravall and B. Rico for their thoughtful comments on earlier versions of this manuscript, M. Sefton for editorial assistance and the many colleagues who have shared their thoughts on this topic, including all the members of my laboratory. Our work is supported by grants from the Spanish Ministry of Science and Innovation (SAF2008-00770, SAF2009-08049-E and CONSOLIDER CSD2007-00023), the Brain and Behaviour Research Foundation (NARSAD) and the Fundació La Marató.

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Glossary

Pyramidal cells

Pyramidal cells are the principal neurons of the cerebral cortex — constituting 80% of the total number of neurons in this brain region — and use glutamate as a neurotransmitter.

GABAergic interneurons

GABAergic interneurons have diverse morphologies but are typically aspiny and localized to the cerebral cortex. They constitute 20% of the total number of neurons in this region.

Axon initial segment

(AIS). The axon initial segment is the proximal end of the axon, close to the neuron soma, and is where action potentials are generated.

Oscillatory activity

Oscillatory activity comprises rhythmic or repetitive neural activity that enables coordinated activity during normal brain functioning.

Gamma-frequency

The gamma frequency constitutes a type of neural oscillation and occurs at a prototypical frequency of approximately 40 Hz, although it may range from 30 to 80 Hz.

Forebrain

The forebrain is the most anterior region of the brain and includes the diencephalon as well as the telencephalon. The basal ganglia, the amygdala and the cerebral cortex are all parts of the telencephalon.

Cannabis

Cannabis is a genus of plants that contain high levels of Δ9-tetrahydrocannabinol, a psychoactive substance that acts as a partial agonist of cannabinoid receptors in the brain and that is responsible for the stimulating effect that is associated with cannabis-derived drugs.

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Marín, O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci 13, 107–120 (2012). https://doi.org/10.1038/nrn3155

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