Recent advances in understanding the mechanisms of cerebellar granule cell development and function and their contribution to behavior

Abstract

The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum's diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. Two major questions arise: what types of cells mediate these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire an emerging view for how granule cells contribute to the shaping of complex animal behaviors.

Keywords: Cerebellum; Purkinje cell; behavior; development; granule cell; in vivo electrophysiology.

Figure 1.. Architecture of the cerebellar cortical circuit.

A three-dimensional schematic of the cerebellar cortex illustrates the repeating basic circuit of Purkinje cells (blue), granule cells (green), climbing fiber afferents (red), mossy fiber afferents (magenta), stellate and basket cell interneurons (black), Golgi cell interneurons (gray), and unipolar brush cell interneurons (orange). Granule cell axons ascend to bifurcate into parallel fibers along the mediolateral axis that contact the dendrites of Purkinje cells. Purkinje cell axons deliver the output of the circuit to the cerebellar nuclei, which are the final output of the cerebellum to the rest of the nervous system. However, a small number of Purkinje cells project directly to the vestibular nuclei. For simplicity, we have not shown Lugaro cells or candelabrum cells. A, anterior; gl, granular layer; M, medial; ml, molecular layer; L, lateral; P, posterior; pcl, Purkinje cell layer.

Figure 2.. Morphology of the granule cell axons and dendritic claws.

( A) Genetically labeled parallel fibers (white arrowheads) traversing the molecular layer along the mediolateral axis. A portion of a genetically labeled Purkinje cell dendritic arbor is also visible (magenta arrowhead). In this three-dimensional reconstruction, the pseudocoloring encodes the depth along the z-axis of the tissue section; the red pseudocolor indicates structures that are closest to the surface, and the blue pseudocolor indicates deeper structures. ( B) A single granule cell labeled using the Golgi-Cox method. The dendrites and claws are revealed in exquisite detail. Scale bar = 10 μm. ( C) A schematic depicting the structures shown in ( A) and ( B). Black arrowheads point to parallel fibers. c, claw; d, dendrite; gl, granular layer; ml, molecular layer; pcl, Purkinje cell layer; s, soma.

Figure 3.. Development of the cerebellar cortical layers.

( A) A schematic depicting the embryonic brain with the cerebellum highlighted in color. ( B) A sagittal section from an embryonic day 16 brain with the cell bodies of neurons labeled using a Nissl stain (violet). The densely labeled external granular layer (green arrowhead, egl) and rhombic lip (green arrowhead, rl) are visible. ( C) A schematic depicting the adult brain with the cerebellum highlighted in color. ( D) A sagittal section from an adult brain with the cell bodies of neurons labeled using a Nissl stain (violet) and Purkinje cells labeled using calbindin immunohistochemistry (brown). The densely labeled granule cells are visible in the innermost layer of the cerebellar cortex, and the Purkinje cell somas and dendrites are visible in the outer layers of the cerebellar cortex. Roman numerals identify the 10 lobules. ( E) A magnified view of ( D). Scale bars = ( B) 100 μm, ( D) 500 μm, and ( E) 50 μm. BS, brainstem; Cb, cerebellum; cp, choroid plexus; Ctx, cerebral cortex; gl, granular layer; Mb, midbrain; ml, molecular layer; pcl, Purkinje cell layer; SC, spinal cord.