Genetic and activity-dependent mechanisms underlying interneuron diversity

Abstract

The proper construction of neural circuits requires the generation of diverse cell types, their distribution to defined regions, and their specific and appropriate wiring. A major objective in neurobiology has been to understand the molecular determinants that link neural birth to terminal specification and functional connectivity, a task that is especially daunting in the case of cortical interneurons. Considerable evidence supports the idea that an interplay of intrinsic and environmental signalling is crucial to the sequential steps of interneuron specification, including migration, selection of a settling position, morphogenesis and synaptogenesis. However, when and how these influences merge to support the appropriate terminal differentiation of different classes of interneurons remains uncertain. In this Review, we discuss a wealth of recent findings that have advanced our understanding of the developmental mechanisms that contribute to the diversification of interneurons and suggest areas of particular promise for further investigation.

Fate and freedom in developing neocortical circuits

“…These interneurons play a pivotal role in the gating and spread of cortical signals through processes such as feedforward inhibition, dis-inhibition and feedback inhibition. This diverse neuronal population, and its role in cortical information processing has been described in a recent review15, and they will not be covered in detail here.…”

“…As mentioned earlier, the latter cell type will not be discussed in detail here since their development and input-dependent circuit integration have recently been reviewed15…”

Early emergence of cortical interneuron diversity in the mouse embryo

“…Although a picture about cortical interneuron cell types is emerging (7, 8), the mechanisms that generate interneuron diversity remain controversial. One model proposes that interneurons acquire the potential to differentiate into a distinct subtype at the level of progenitors or shortly after becoming postmitotic, before they migrate; the competing model postulates that interneuron identity is established relatively late in development, after they have migrated to their final location, through interactions with the cortical environment (9). …”

“…This suggests that interneuron diversity does not emerge in response to activity-dependent mechanisms in the cortex (1, 9), but rather is established early, before these cells reach the cortex, by specific transcriptional programs that then unfold over the course of several weeks. Activity-dependent mechanisms undoubtedly influence development, maturation and plasticity of cortical interneurons (24–26), but most aspects that are directly linked to the functional diversity of cortical interneurons seem to be intrinsically determined (14, 27).…”

Developing neurons are innately inclined to learn on the job

“…The expression of cer tain genes remains conserved in specific types of interneuron from their birth through to adulthood 4 , whereas others affect interneuron maturation more transiently dur ing early embryonic development 5 . Such intrinsic processes are thought to cooperate with the interneuron's environment to establish neuronal circuits and brain connectivity in the adult 6 . For example, after arrival in the cortex, neuronal activity affects several aspects of interneuronal development [7][8][9] .…”