Quantitative morphological analysis of the neostriatum and the cerebellum of tenascin-C deficient mice

Abstract

Tenascin-C (TNC) is an extracellular matrix glycoprotein abundantly expressed in neural and non-neural tissues during normal development, repair processes in the adult organism and tumourigenesis. In the central nervous it has been implicated in cell proliferation, neural cell migration, axonal growth and guidance, synaptic plasticity and neurotransmitter systems related to behaviour. Mice deficient in TNC show a range of physiological and behavioural abnormalities. This study was designed to further characterize the tenascin-C deficient mouse with respect to morphological abnormalities in striatum and the cerebellum. Performed were stereological estimations of immunohistochemically identified major cell types and morphometric analysis of the striatal volume and the thickness of the cerebellar cortex. Furthermore, the inhibitory GABA-mediated inputs to Purkinje cells were quantitatively analysed. The results showed normal striatal volume and molecular and granular layer thickness in TNC deficient mice as well as normal total numbers of neurons and normal numbers of cholinergic interneurons, oligodendrocytes and microglia. In the striatum of TNC-/- mice, a decrease in the number of parvalbumin-positive interneurons was detected and astrocytes were more numerous that in wild-type littermates. In the cerebellum of adult TNC deficient mice, a marked increase in the number of PV+ interneurons (stellate and basket cells) was found and, as in the case of the striatum, the number of astrocytes was abnormally high in TNC-/- mice. Perisomatic and dendritic inhibitory inputs to Purkinje cells were similar in TNC deficient and wild-type animals. The results of this study show that deficient expression of tenascin-C leads to the formation of an abnormally small population of PV+ interneurons in the striatum, what might be due to disturbances in tangential migration, cell proliferation and/or cell death during brain development and maturation. Loss of PV-positive interneurons may be partly responsible for previously reported behavioural deficits in TNC-/- mice. In contrast to the striatum, the number of parvalbumin-positive stellate and basket cells in the cerebellum was markedly increased. This finding might be attributed to a different origin and a different level of tenascin-C expression along the migration route of stellate and basket cells, as compared to PV+ interneurons in the striatum. It seems likely that the abnormally high density of astrocytes in both brain regions is due to a loss of auto/paracrine control of astrocyte proliferation after TNC gene ablation. This study shows that TNC is involved in regulating the size of interneuron and astrocyte populations and is indispensable for normal brain development.