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Mammalian forebrain interneurons maintain plasticity

07 February 2012

Scientists at NIMR have shown that interneurons of the mammalian forebrain, and perhaps many other neurons in the mammalian brain, maintain remarkable phenotypic plasticity. The research is published in PNAS.

The information processing ability of the brain is vital in order for animals to respond to a constantly changing environment and maintain internal homeostasis. Underpinning both functions is the formation of complex and highly integrated neuronal circuits, made up of many different subtypes of interconnected neurons that are generated in the right number and proportions, mostly during development. Scientists have learnt much about the genes and proteins that are required for the generation of different neuronal cell populations. In contrast, the molecular mechanisms that maintain the identity of neurons after they have differentiated and become wired-up into functional networks, are less well understood. The characterization of such mechanisms is important if we want to understand the plasticity of the nervous system and ultimately influence its ability to adjust during development, disease or injury.

To address the mechanisms that regulate the generation and phenotypic stability of neurons, the lab of Vassilis Pachnis (pictured), from NIMR’s Division of Molecular Neurobiology, has been studying the transcriptional mechanisms that control the development of the striatum. This is an area of the brain that integrates multiple cortical and subcortical inputs and relays information to many other brain structures. Balanced striatal output is critical for motor co-ordination and cognitive activity and depends to a large extent on local circuits that are controlled by two distinct subpopulations of striatal neurons, the GABA-producing (GABAergic) interneurons and the acetylcholine-producing (cholinergic) interneurons. Previous studies from this lab showed that both groups of striatal interneurons are derived from a common undifferentiated precursor, which expresses the closely related LIM homeodomain transcription factors Lhx6 and Lhx7. Later genetic studies from the group also showed that Lhx7 is important for the generation of cholinergic interneurons while Lhx6 is instrumental for directing the formation of the different types of GABAergic interneurons of the striatum. Although the role of Lhx6 and Lhx7 in the initial generation of striatal interneurons has been clearly established, their potential role in maintaining the unique morphological and molecular properties of these neuronal subtypes at subsequent developmental stages and in adult animals remained unclear.

By combining in vivo fate mapping and phenotypic analysis of mutant and transgenic mice, Rita Lopes and her colleagues in the Pachnis lab have demonstrated that Lhx7 is essential not only for the initial generation of cholinergic striatal interneurons, but also for maintaining their morphological and molecular characteristics at later developmental stages and perhaps throughout life. Ablation of Lhx7 from already specified cholinergic neurons resulted in loss of cholinergic characteristics and acquisition of GABAergic properties. Moreover, their studies suggested specific molecular mechanisms by which the antagonistic relationship between transcription factors controls the early differentiation choices of striatal interneuron precursors. These results raise the possibility that neuronal cell identities in the brain can be readjusted or reversed at all developmental stages and in adult animals by manipulating the levels of key transcriptional regulators.

Our results show that interneurons of the mammalian forebrain, and perhaps many other neurons in the mammalian brain, maintain remarkable phenotypic plasticity beyond cell cycle exit and commitment to terminal identity. By retaining phenotypic plasticity beyond their initial specification, forebrain neurons could contribute to the ability of the CNS to cope with dynamic changes imposed by developmental requirements, learning, or disease.

Vassilis Pachnis