Heterogeneity of Purkinje cells (PCs) that are arranged into discrete longitudinal stripes in the cerebellar cortex is related to the timing of PC generation. To understand the cerebellar compartmental organization, we mapped the PC birthdate (or differentiation timing) in the entire cerebellar cortex. We used the birthdate-tagging system of neurog2-CreER (G2A) mice hybridized with the AldocV strain which clarifies the zebrin (aldolase C) longitudinal striped pattern.The pattern of the birthdate-dependent PC distribution was arranged consistently into longitudinally-oriented stripes throughout almost all lobules except for the nodulus, paraflocculus and flocculus, in which distinct stripes were observed. Boundaries of the PC birthdate stripes were found either in the middle or coincided with that of the zebrin stripes. PCs in each birthdate stripe were born in various periods between embryonic day (E) 10.0 and E 13.5.In the vermis, PCs were chronologically distributed from lateral to medial stripes. In the paravermis, PCs of early birthdates were distributed in the long lateral zebrin-positive stripe (stripe 4+//5+) and the medially neighboring narrow zebrinnegative substripe (3d-//e2-), while PCs of late birthdates were distributed in the rest of all paravermal areas. In the hemisphere, PCs of early and late birthdates were intermingled in the majority of areas.The results indicate that the birthdate of a PC is a partial determinant for the zebrin compartment in which it is located. However, the correlation between the PC birthdate and the zebrin compartmentalization is not simple, and distinct among the vermis, paravermis, hemisphere, nodulus, and flocculus.
Summary In the cerebellar cortex, heterogeneous populations of Purkinje cells (PCs), classified into zebrin (aldolase C)-positive (Z+) and -negative (Z-) types, are arranged into separate longitudinal zones. They have different topographic neuronal connections and show different patterns of activity in behavior tasks. However, whether the zebrin type of PCs directly links with the physiological properties of the PC has not been well clarified. Therefore, we applied in vitro whole-cell patch-clamp recording in Z+ and Z- PCs in vermal and hemispheric neighboring zebrin zones in zebrin-visualized mice. Intrinsic excitability is significantly higher in Z- PCs than in Z+ PCs. Furthermore, intrinsic plasticity and synaptic long-term potentiation are enhanced more in Z- PCs than in Z+ PCs. The difference was mediated by different modulation of SK channel activities between Z+ and Z- PCs. The results indicate that cellular physiology differentially tunes to the functional compartmentalization of heterogeneous PCs.
Heterogeneity of Purkinje cells (PCs) that are arranged into discrete longitudinal stripes in the cerebellar cortex is related to the timing of PC generation. To understand the cerebellar compartmental organization, we mapped the PC birthdate (or differentiation timing) in the entire cerebellar cortex. We used the birthdate-tagging system of neurog2-CreER (G2A) mice hybridized with the AldocV strain which clarifies the zebrin (aldolase C) longitudinal striped pattern.The pattern of the birthdate-dependent PC distribution was arranged consistently into longitudinally-oriented stripes throughout almost all lobules except for the nodulus, paraflocculus and flocculus, in which distinct stripes were observed. Boundaries of the PC birthdate stripes were found either in the middle or coincided with that of the zebrin stripes. PCs in each birthdate stripe were born in various periods between embryonic day (E) 10.0 and E 13.5.In the vermis, PCs were chronologically distributed from lateral to medial stripes. In the paravermis, PCs of early birthdates were distributed in the long lateral zebrin-positive stripe (stripe 4+//5+) and the medially neighboring narrow zebrinnegative substripe (3d-//e2-), while PCs of late birthdates were distributed in the rest of all paravermal areas. In the hemisphere, PCs of early and late birthdates were intermingled in the majority of areas.The results indicate that the birthdate of a PC is a partial determinant for the zebrin compartment in which it is located. However, the correlation between the PC birthdate and the zebrin compartmentalization is not simple, and distinct among the vermis, paravermis, hemisphere, nodulus, and flocculus.
One of the notable characteristics of the functional localization in the cerebellar cortex is the dual representation of the body (somatotopy) along with its anterior-posterior axis. This somatotopy is conspicuous in the C1/C3 module, which is demarcated as the multiple zebrin-negative and weekly-positive stripes in dual paravermal areas in anterior and posterior lobules within the cerebellar compartments. In this report, we describe the early formation process of the cerebellar compartmentalization, particularly in the C1/C3 module. As developing PCs guide formation of the module-specific proper neuronal circuits in the cerebellum, we hypothesized that the rearrangement of embryonic Purkinje cell (PC) clusters shapes the adult cerebellar compartmentalization. By identifying PC clusters with immunostaining of marker molecules and genetical birthdate-tagging with Neurog2-CreER (G2A) mice, we clarified the three-dimensional spatial organization of the PC clusters and tracked the lineage relationships among the PC clusters from embryonic day 14.5 (E14.5) till E17.5. The number of recognized clusters increased from 9 at E14.5 to 37 at E17.5. Among E14.5 PC clusters, the c-l (central-lateral) cluster which lacked E10.5-born PCs divided into five c-l lineage clusters. They separately migrated underneath other clusters and positioned far apart mediolaterally as well as rostrocaudally by E17.5. They were eventually transformed mainly into multiple separate zebrin-negative and weakly-positive stripes, which together configured the adult C1/C3 module, in the anterior and posterior paravermal lobules. The results indicate that the spatial rearrangement of embryonic PC clusters is involved in forming the dual somatotopic areas in the adult mouse paravermal cerebellar cortex. Significance statement Genetically programmed morphogenetic processes in the embryonic brain can form a highly organized anatomical complex in the postnatal brain. The adult cerebellum has a complex functional localization; one of the challenging aspects of which is the dual representation of somatosensorimotor function in both the anterior and posterior paravermal areas. To elucidate morphogenetic processes of the intricate organization of the cerebellar cortex, we tracked lineages of early cerebellar PC clusters by birthdate-tagging methods. Starting with nine clusters at embryonic day 14.5, we clarified the differentiation of lineage of all clusters in later stages. Our results indicate that the spatial differentiation of embryonic PC clusters is involved in forming the basic cerebellar organization of the mouse brain.
Heterogeneous populations of cerebellar Purkinje cells (PCs) are arranged into separate longitudinal stripes, which have different topographic afferent and efferent axonal connections presumably involved in different functions, and also show different electrophysiological properties in firing pattern and synaptic plasticity. However, whether the differences in molecular expression that define heterogeneous PC populations affect their electrophysiological properties has not been much clarified. Since the expression pattern of many of such molecules, including glutamate transporter EAAT4, replicates that of aldolase C or zebrin II, we recorded from PCs of different “zebrin types” (zebrin-positive = aldolase C-positive = Z+; and Z−) in identified neighboring stripes in vermal lobule VIII, in which Z+ and Z− stripes occupy similar widths, in the Aldoc-Venus mouse cerebellar slice preparation. Regarding basic cellular electrophysiological properties, no significant differences were observed in input resistance or in occurrence probability of types of firing patterns between Z+ and Z− PCs. However, the firing frequency of the tonic firing type was higher in Z− PCs than in Z+ PCs. In the case of parallel fiber (PF)-PC synaptic transmission, no significant differences were observed between Z+ and Z− PCs in interval dependency of paired pulse facilitation or in time course of synaptic current measured without or with the blocker of glutamate receptor desensitization. These results indicate that different expression levels of the molecules that are associated with the zebrin type may affect the intrinsic firing property of PCs but not directly affect the basic electrophysiological properties of PF-PC synaptic transmission significantly in lobule VIII. The results suggest that the zebrin types of PCs in lobule VIII is linked with some intrinsic electrophysiological neuronal characteristics which affect the firing frequency of PCs. However, the results also suggest that the molecular expression differences linked with zebrin types of PCs does not much affect basic electrophysiological properties of PF-PC synaptic transmission in a physiological condition in lobule VIII.
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