Interneuron Integration and Synapse Formation

In one of the most remarkable events in neural development, newly born interneurons disperse throughout the brain to populate strikingly distinct structures including the cortex, hippocampus, striatum and amygdala. Our recent studies suggest that relegation to a particular neural structure is stochastic rather than determined (Fishell and Kepec, 2014; Mayer et al., in preparation), suggesting that the further refinement of interneuron identity relies upon local cues received upon their integration into particular structures. This presents us with the challenge of understanding how specific subtypes acquire region-specific identity, most notably their specific afferent and efferent connectivity. Recent work in our laboratory suggests that local patterns of neuronal activity are essential in bestowing regional character on particular interneuron subtypes (DeMarco et al., 2011, submitted). Understanding E-T (electrical to transcriptional) coupling mechanisms whereby interneurons acquire their local character and connectivity is a central emerging theme in our research. Ongoing projects in the laboratory are focused on examining modes of calcium entry into developing interneurons and how this results in the transcription of particular gene targets, as well as the recruitment of post-transcriptional mechanisms such as activity-controlled alternative splicing, which may tailor the transcriptome to promote the maturation and the integration of interneuron subtypes into developing cortical circuits. As it seems evident that developmentally regulated genetic programs (investigated in topic 1) cannot account for the whole array of interneuron types and their associated patterns of connectivity, we expect that these approaches will help unravel the daunting question of how local circuit assembly is achieved.

Example I - Information of the tactile sensation flows from whisker follicles to the somatosensory cortex via brain stem and thalamus. Plucking whiskers of the animals leads to the dampening of neuronal activity in the somatosensory cortex. The decrease in the excitatory input of the thalamocortical afferents leads to the defect in the proper maturation of the neurogliaform interneurons. The image shows the effect of whisker plucking on the morphology of the neurogliaform interneuron. (Image & Description provided by Rashi Priya)

Example II - Early in post-natal development GABAergic inhibitory neurons form synapses onto the cell soma and dendrites of pyramidal neurons and other neighboring interneurons. The image depicts a staining of Layer 5 inhibitory synapses in a Dlx6aCre, Ai9 brain with interneurons labeled in red, VGAT (vesicular GABA transporter localizes only to the pre-synaptic active zone) labeled in green and Gephyrin (the predominant post-synaptic scaffold molecule only for inhibitory synapses) labeled in blue. One can appreciate classic PV+ Basket cell synapses targeting the soma of excitatory pyramidal neurons and interneurons (in red), as well as dendritic targeted inhibitory synapses. (Image provided by Brie Wamsley)

Example III - Mice expressing SSTCRE; R26R-HTB are injected with the modified rabies virus (EnvA)SAD-dG-mCherry targeting the somatosensory cortex. SST-cIN specific somatosensory infection of monosynaptic retrograde rabies virus allows mapping of the afferent connectivity to SST-cINs during early postnatal periods. The image shows the thalamocortical axons projected from the ventrobasal thalamic nuclei neurons innervating the SST-cINs in cortex at P6. (Image & Description provided by Sebnem Tuncdemir)

Example IV - How much of Interneuron Connectivity is Custom Made during Development? The magnitude of diversity within cortical interneuron populations is only surpassed by their cell-type specific wiring. The development of sub-type specific synaptic wiring relies on genetically determined mechanisms and is subjected to activity-dependent modification. We can target specific interneuron cell types by utilizing intersectional, cre- and tet -dependent genetic labeling of pre- and post-synaptic structures to assess how afferent and efferent synaptic structures are affected by modulating early sensory experiences and/or loss of early activity-regulated genes. The images illustrates mosaic expression of an axonal label in SST+ Martinotti cells within the somatosensory cortex. (Image provided by Brie Wamsley)

Selected References

Miyoshi G, Fishell G. GABAergic interneuron lineages selectively sort into specific cortical layers during early postnatal development. Cereb Cortex. 2011 Apr;21(4):845-52. Epub 2010 Aug 23. Download PDF

Fishell G, Rudy B. Mechanisms of inhibition within the telencephalon: "where the wild things are". Annu Rev Neurosci. 2011;34:535-67. Download PDF

De Marco García NV, Karayannis T, Fishell G. Neuronal activity is required for the development of specific cortical interneuron subtypes. *equal contribution. Nature. 2011 Apr 21;472(7343):351-5. Epub 2011 Apr 3. Download PDF

Picardo MA, Guigue P, Bonifazi P, Batista-Brito R, Allene C, Ribas A, Fishell G, Baude A, Cossart R. Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus. Neuron. 2011 Aug 25;71(4):695-709. Download PDF

Karayannis T, De Marco García NV, Fishell G. Functional adaptation of cortical interneurons to attenuated activity is subtype-specific. Front Neural Circuits. 2012 Sep 24;6:66. eCollection 2012. Download PDF

Close J, Xu H, De Marco García N, Batista-Brito R, Rossignol E, Rudy B, Fishell G. Satb1 is an activity-modulated transcription factor required for the terminal differentiation and connectivity of medial ganglionic eminence-derived cortical interneurons. J Neurosci. 2012 Dec 5;32(49):17690-705. Download PDF

Kepecs A, Fishell G. Interneuron cell types are fit to function. Nature. 2014 Jan 16;505(7483):318-26. Download PDF