MicroRNAs Regulate Synaptic Strength at Calyx of Held
Constanze Krohs, Christoph Körber, Lena Ebbers, Faiza Altaf, Giulia Hollje, et al.
(see pages 6796–6811)
MicroRNAs (miRs) fine tune protein expression by binding to and repressing translation of target mRNAs. Several miRs have important roles in nervous system development and function, including a cluster of three miRs (miR-96, miR-182, and miR-183) that are present on the same transcript and are coexpressed in many sensory cells. Notably, point mutations in the so-called seed region of miR-96—a region that mediates target recognition and binding—cause progressive hearing loss in humans and in Diminuendo (Dmdo) mice. In Dmdo mice, hearing loss is accompanied by hair-cell degeneration, volume reduction in auditory brainstem nuclei, and abnormal spiking and synaptic properties at calyx of Held synapses in the auditory brainstem. Krohs, Körber, et al. now show that knocking out miR-96 and miR-183 has additional effects on auditory system development.
Like in Dmdo mice, the volumes of multiple auditory nuclei were smaller than normal in miR-96/183-deficient mice. Unlike in Dmdo mice, however, the amplitudes of spontaneous and evoked EPSCs at calyx of Held synapses were much larger than normal in knock-out mice. This potentiation was attributable partly to an increase in the quantal content of synapses, which resulted from an increase in the size of the readily releasable pool of vesicles. Vesicle release probability, synaptic vesicle size, and active-zone length appeared unchanged, however. Postsynaptic changes may have also contributed to the increased EPSC amplitude in miR-96/183-null mice. Like in Dmdo mice, but unlike in wild-type mice, NMDA receptor currents contributed to EPSCs in calices of miR-96/183-null mice. In addition, postsynaptic clusters of the AMPA receptor subunit GluA1 and the scaffolding protein Homer1—two known targets of miR-96—were larger in 96/183-null calyx of Held synapses than in controls.
These results suggest that loss of miR-96/183 leads to an increase in the strength of calyx of Held synapses by increasing both the size of the readily releasable pool of vesicles in presynaptic terminals and the number and type of glutamate receptors in the postsynaptic density. Future work should elucidate which targets of miR-96 and miR-183 regulate these properties and how the miRs work together to ensure that the calyx of Held functions normally.
In wild-type mice (left), thalamocortical axons extend into the subplate and wait several days before entering the cortical plate. When Lhx2 was deleted from neural progenitors at E11.5 (right), thalamocortical axons entered the cortex prematurely, extending as far as the marginal zone. See Pal et al. for details.
Barrel Formation Depends on Lhx2 in Subplate Progenitors
Suranjana Pal, Deepanjali Dwivedi, Tuli Pramanik, Geeta Godbole, Takuji Iwasato, et al.
(see pages 6822–6835)
The cerebral cortex can be divided into numerous functional areas that have distinct cytoarchitecture, connectivity, and gene expression profiles. Differentiation of cortical areas during development depends heavily on synaptic input from the thalamus. In the rodent somatosensory system, for example, ingrowing bundles of thalamocortical axons carrying information about single whiskers instruct the formation of cortical barrels. But the ability of thalamocortical axons to shape cortical architecture is governed by gene expression profiles in neurons. These profiles are established by gradients of signaling molecules that drive regionalized expression of homeobox transcription factors in neural progenitors. Selective deletion of one such transcription factor, Lhx2, in cortical progenitors prevents the formation of barrel fields (Shetty et al., 2013, Proc Natl Acad Sci U S A 110:E4913). Surprisingly, Pal et al. show that the lack of barrels results not from loss of Lhx2 in progenitors of the layer IV neurons that normally form barrel walls, but from its loss in progenitors of subplate neurons—a transient population that lies below the developing cortex.
Besides disrupting postnatal barrel formation, knocking out Lhx2 in cortical progenitors disrupted the growth of thalamocortical axons during embryonic development. Thalamocortical axons normally extend below the cortical plate (in the subplate) starting on embryonic day 15.5 (E15.5) in mice. The axons form synapses with subplate neurons and remain there for several days before extending into the cortex. When Lhx2 was deleted from cortical progenitor neurons (including subplate progenitors) on E11.5, thalamocortical axons did not pause at the subplate; instead, they grew into the cortex prematurely, extending across all layers. Remarkably, such exuberant growth did not occur when Lhx2 was deleted from neural progenitors starting at E12.75 or when Lhx2 was deleted from postmitotic neurons.
Given that the generation of subplate neurons peaks at E11.5 and cortical neurons are generated subsequently, these results suggest that Lhx2 expression in subplate progenitors is required for timely growth of thalamic afferents into the cortical plate. Gene expression analysis revealed that loss of Lhx2 in progenitors altered expression of ion channels and synaptic proteins in postmitotic subplate neurons, resulting in reduced excitability and spiking. This may have disrupted synaptic interactions that are required for organizing thalamocortical axons and for preventing premature growth into the cortex.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
