Target and neurotransmitter specificity of fetal central nervous system transplants: importance for functional reinnervation

Abstract

The ability of grafted fetal ventral mesencephalic dopaminergic (DAergic) neuroblasts to reinnervate the unilaterally DA denervated rat striatum and improve motoric asymmetry has been well documented in several laboratories. The importance of host target specificity, and catecholamine (CA) neurotransmitter species, in the ability of grafts to ameliorate rotational responses to apomorphine and to affect electrophysiological characteristics of striatal neurons has not been systematically studied. We unilaterally lesioned Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA) and verified the lesions using apomorphine (0.05 mg/kg, s.c.)-induced rotational behavior. Some of the animals subsequently received, intrastriatally, either DA neuroblasts from ventral mesencephalon that normally innervate the striatum, or from arcuate nucleus that do not. Additionally, two other groups were included that received either a CAergic graft from the noradrenergic nucleus locus coeruleus or a graft of cerebral cortex, which normally projects to the striatum but does not contain CAergic neurons. Only the fetal ventral mesencephalic grafts were able to reduce apomorphine- induced rotations and normalize striatal cell firing rates; striatal cell firing rates with ventral mesencephalic grafts were 1.43 Hz +/- 0.22, with arcuate nucleus grafts were 6.03 +/- 0.73, with locus coeruleus grafts were 4.71 +/- 0.74, and with cerebral cortex grafts were 4.36 +/- 0.45. Moreover, only the ventral mesencephalic grafts produced a dense tyrosine hydroxylase (TH)-immunoreactive nerve terminal network in the striatum; in contrast, the arcuate nucleus grafts did not reinnervate the striatum. In locus coeruleus grafted striata, few very long TH-positive axons were seen. We thus conclude that target specificity and neurotransmitter type are critically important in the ability of a graft to functionally reinnervate the 6- OHDA denervated striatum.

Identification of Dopaminergic Neurons of Nigral and Ventral Tegmental Area Subtypes in Grafts of Fetal Ventral Mesencephalon Based on Cell Morphology, Protein Expression, and Efferent Projections

“…These differences are observed not only when comparing the axonal outgrowth from different types of grafted neurons (differing with respect to their transmitter phenotype) but also between subtypes of neurons using the same neurotransmitter, such as different subtypes of cholinergic neurons transplanted to the hippocampus (Nilsson et al, 1988;Clarke et al, 1990) or different subtypes of serotonergic neurons transplanted to striatum or spinal cord (Foster et al, 1985;Foster et al, 1988). This holds true for different types of dopaminergic neurons, as shown by the present data comparing fiber outgrowth from different subtypes of mesencephalic DA neurons and those of Zuddas et al (1991) and Hudson et al (1994) comparing the extent of fiber outgrowth from diencephalic and mesencephalic DA neurons. The mechanisms underlying this neuron-specific growth regulation in the postnatal or adult CNS are poorly known.…”

“…This property is not shared by all DA neuroblasts: only cells derived from the ventral mesencephalon (VM) that innervate the striatum are able to establish an extensive terminal network in the host striatum. DA neuroblasts taken from other developing brain regions do not share this property (Abrous et al, 1988;Zuddas et al, 1991;Hudson et al, 1994).…”

Doublesex and mab-3–related transcription factor 5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral-medial progenitor fate

“…The immunostaining and global gene-expression analysis shown here demonstrates that Dmrt5 guards the medial domain identity by restricting ventral progenitors to an accurate medial mDA fate. Given that acquisition of midbrain regional identity is critical for successful functional integration in cell therapy (29), our finding that Dmrt5 enforces a midbrain fate would have important implications in directed stem cell differentiation.…”

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

“…The behavioral effects of transplantation in rats are specific to mesencephalic dopamine cells. Rats transplanted with serotonergic neurons from mesencephalic raphe or dopamine neurons from hypothalamus have no improvement in behavior [17,18]. These experiments showed that innervation of the target is a specific interaction between the appropriate dopamine neuron and factors released from the denervated striatum.…”