Origin, Development, and Synaptogenesis of Cortical Interneurons

Abstract

The mammalian cerebral cortex represents one of the most recent and astonishing inventions of nature, responsible of a large diversity of functions that range from sensory processing to high-order cognitive abilities, such as logical reasoning or language. Decades of dedicated study have contributed to our current understanding of this structure, both at structural and functional levels. A key feature of the neocortex is its outstanding richness in cell diversity, composed by multiple types of long-range projecting neurons and locally connecting interneurons. In this review, we will describe the great diversity of interneurons that constitute local neocortical circuits and summarize the mechanisms underlying their development and their assembly into functional networks.

Keywords: brain; cell death; cortex; development; interneuron; neuron; synaptogenesis.

Figure 1

Interneuron diversity in the murine neocortex. (A) Cortical interneurons can be classified into three main classes: PV, SST, and 5Htr3a. Each of these classes can be further subdivided into different types. (B) Different interneuron types preferentially target specific compartments of surrounding projection neurons. Basket cells target their soma. Chandelier cells specifically innervate axon initial segments. SST and 5Htr3a cells mostly target projection neuron dendrites at different levels. PV, parvalbumin; SST, somatostatin; NGF, neurogliaform; NPY, neuropeptide Y; CCK, cholecystokinin.

Figure 2

Neurogenesis in the mouse medial ganglionic eminence. (A) Diverse types of progenitor cells underlie the genesis of cortical interneurons in the embryonic subpallium. Apical progenitors reside in the VZ and divide to generate neurons and basal progenitors. Basal progenitors migrate to the SVZ where they divide to generate post-mitotic interneurons. These neurons then migrate to the MZ and leave the MGE to invade the developing cortex. Cx, cortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; VZ, ventricular zone; SVZ, subventricular zone; MZ, marginal zone.

Figure 3

Fate-specification of cortical interneurons. (A) The spatially organized expression of specific combinations of transcription factors subdivides the subpallium into different structures. Among those, the MGE and POA generate interneurons of both PV and SST classes. The CGE and POH are responsible for the generation of all types of 5Htr3a neurons. (B) MGE is further subdivided into spatial domains in the dorsoventral axis, each of these domains is defined by differential gene expression patterns. Such spatial patterning relates to the production of different interneuron types, as SST and PV cells largely derive from dorsal and ventral MGE respectively. (C) Temporal biases in interneuron origin. SST cells are mostly produced during early neurogenesis, while PV cell production remains nearly constant throughout the entire neurogenic window. (D) Progenitor cell mode of division also influences interneuron fates. Direct neurogenesis from apical progenitors mostly produces SST cells, while basal progenitor divisions mostly generate PV fates. MGE, medial ganglionic eminence; POA, preoptic area; CGE, caudal ganglionic eminence; POH, Preoptic-hypothalamic border domain; PV, parvalbumin; SST, somatostatin; CB, calbindin; CR, calretinin; NOS, nitric oxide synthase; CCK, cholecystokinin; VIP, vasointestinal peptide; NDNF, neuron derived neurotrophic factor; NPY, neuropeptide Y.

Figure 4

Interneuron migration and integration. (A) Upon born, non-mitotic cortical Interneurons migrate through the subpallium avoiding entering the Striatum, a restrictive area due to chemorepulsive cues, and following a chemoattractive gradient of cues until reaching the final positioning in the cortex. Str, striatum. (B) Laminar allocation and integration into cortical circuits. During the first week, Interneurons allocate into their final laminal position following a period of programmed cell death. Surviving neurons develop synapses according to their type onto Pyramidal Neurons.

Figure 5

Domain-restricted synaptic molecules. (A) Levels for Cbln4, Lgi2, and Fgf13 increase during development following a IN-type specific molecular program that control domain-restricted synaptogenesis. (B) Synaptic disruption. Loss of the specific synaptogenic molecules during development causes the reduction on the number of synapses onto specific domains of Pyramidal Neurons. (C) Formation of domain-restricted synapses. Ectopic expression of the SST+-specific synaptic molecule Cbln4 in PV+ basket cells promotes the formation of synapses onto the dendrites of Pyramidal Neurons. Cbln4, Cerebellin4; Lgi2, Leucine-rich repeat LGI family member 2; FGF13, Fibroblast Growth Factor 13.