Trends in Neurosciences
Volume 27, Issue 7, 1 July 2004, Pages 400-406
Journal home page for Trends in Neurosciences

Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders

https://doi.org/10.1016/j.tins.2004.05.008Get rights and content

Abstract

Neurodevelopmental disorders typically have complex endophenotypes, which can include abnormalities in neuronal excitability, processing of complex information, as well as behaviors such as anxiety and social interactions. Converging experimental and clinical evidence suggests that altered interneuron development may underlie part of the pathophysiological process of such disorders. Consistent with this, mice with abnormal hepatocyte growth factor signaling exhibit disturbances in the development of specific interneuron subclasses that are paralleled by seizure activity and a complex behavioral phenotype. Mutations in molecules that regulate different aspects of interneuron development could provide the heterogeneity in genetic susceptibility that, when combined with environmental disturbances, results in a phenotypic spectrum that serves as the hallmark pathophysiology for autism, mental retardation, schizophrenia and other neurodevelopmental disorders.

Section snippets

Mechanisms of interneuron development

The classical view of neocortical development, which is built upon a century of descriptive studies, stated that all neocortical neuronal and glial populations arise from the dorsal telencephalic (pallial) proliferative zones, with neurons destined for layers 6 to 2 generated in a temporal fashion to produce an inside-out gradient of birthdates [12]. This mechanism provided an opportunity for projection neurons and interneurons, which would be spatially related by virtue of the location of

The search for molecules that promote interneuron migration

The diversity of interneuron sources in the rodent forebrain is also reflected in the compilation of complex migratory routes, which are most clearly visualized by real-time imaging studies of organotypic forebrain slices, as well as of embryonic brains in situ [28]. The migration of GABAergic cells, and their entry into the developing cortical plate, appears to be well-orchestrated rather than stochastic, raising the fundamental question of what molecular cues guide the movement of interneuron

HGF and forebrain development

The discovery that HGF may serve as an important molecule in forebrain development was unexpected, and led to a series of in vitro and in vivo studies that linked interneuron development and subsequent behavioral dysfunction. HGF was identified initially as a protein, produced in the liver, that promotes the proliferation of hepatocytes, particularly during a tissue regenerative response [37]. In the developing lung, this same bioactivity was discovered independently to promote the movement of

In vivo analysis: circumventing early embryonic lethality of Hgf deletion

Ideally, analysis of mice with targeted deletions of Hgf or the Met receptor genes would have provided the essential in vivo correlates to demonstrate a role for this signaling system in interneuron development. However, both mutations individually cause early embryonic lethality 44, 45 before the major wave of interneuron migration. Generating conditional mutations specifically to forebrain regions would probably circumvent the problem of lethality. These studies are ongoing. An alternative

Functional implications of altered interneuron development – links to schizophrenia and autism

Not surprisingly, the uPAR−/− mice, with a 50% decrease in detectable GABAergic interneurons in frontal, parietal and hippocampal regions, exhibit spontaneous low-amplitude desynchronized electroencephalogram (EEG) activity with abnormal periods of slow waves and interictal discharges, as well as increased susceptibility to convulsants [11]. However, further analysis revealed that the functional phenotype of the uPAR−/− mouse was far more complex than the expression of epileptic seizures. Thus,

Concluding remarks

Disruption of the uPAR and HGF–MET signaling systems results in complex alterations in GABAergic neuron development in the forebrain. Although not typically life-threatening, the susceptibility of interneuron development to genetic and environmental forces could reflect the neurodevelopmental basis of neuropsychiatric disorders that have, at their core, the reduced ability to process complex information. There are a large number of molecular candidates involved in mediating the initial

Acknowledgements

Our research is supported, in part, by NIMH grant MH65299 (to P.L.) and NRSA grant MH12651 (to E.M.P.).

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