Evidence for Enhanced Synaptic Excitation in Transplanted Neostriatal Neurons

doi:10.1006/exnr.1993.1155

Experimental Neurology

Volume 123, Issue 2, October 1993, Pages 222-234

https://doi.org/10.1006/exnr.1993.1155 Get rights and content

Abstract

Fetal neostriatal tissue was transplanted into either the neostriatum or substantia nigra of adult rats. One to 6 months after transplantation, coronal brain slices were taken through the rostrocaudal extent of the transplants and neurons were characterized electrophysiologically using an in vitro slice preparation. When compared to control neurons taken from intact adult neostriata, transplanted neostriatal neurons (TSNs) had higher input resistances and longer time constants. All other passive and active membrane properties assessed were comparable between transplanted and control neostriatal neurons. Regardless of the transplantation site, local extracellular stimulation outside the graft elicited high-amplitude, long-duration depolarizing synaptic potentials that typically triggered bursts of action potentials. These synaptic potentials contrast with lower amplitude, shorter duration synaptic potentials consistently elicited in control neostriatal neurons. The depolarizing synaptic potentials evoked in the TSNs appeared to be mediated by a combined activation of N -methyl-d-aspartate (NMDA) and non-NMDA excitatory amino acid receptors. Both the broad-spectrum excitatory amino acid antagonist kynurenic acid and the specific non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione significantly reduced postsynaptic potentials elicited in TSNs. The specific NMDA antagonist 2-amino-5-phosphonovalerate had less effect on the amplitude but markedly reduced the duration of the synaptic potentials. The duration and amplitude of the bursts were augmented by the γ,-aminobutyric acid (GABA)_A receptor antagonist bicuculline methiodide, indicating that inhibition occurred in TSNs. TSNs were also more sensitive than control neurons to direct application of glutamate or NMDA. These findings demonstrate that TSNs express altered electrophysiological properties. The pharmacological analysis indicates that depolarizing postsynaptic potentials were mediated by activation of excitatory amino acid receptors, suggesting either innervation of the graft by host fibers which contain excitatory amino acids or development of novel local excitatory interactions intrinsic to the graft. Furthermore, the occurrence of high-amplitude, long-duration depolarizing synaptic potentials in TSNs, regardless of the site of transplantation, suggests that grafted neostriatal neurons become hyperexcitable to synaptic input.

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Cited by (9)

Role of experience, training, and plasticity in the functional efficacy of striatal transplants
2012, Progress in Brain Research
Citation Excerpt :
Furthermore, the morphological and cellular response to enrichment can be interpreted as an index of the grafted cells’ degree of reconnectivity with excitatory cortical inputs. Electrophysiological and neurochemical analyses of graft tissue have demonstrated that (a) transplanted neurons display similar electrophysiological properties as observed in the intrinsic cellular population; (b) host neurons can signal patterned information to grafted cells; and (c) using both in vitro and in vivo approaches, transplanted striatal neurons can respond to stimulation of the host cortex and thalamus (Rutherford et al., 1987; Siviy et al., 1993; Walsh et al., 1988; Wilson et al., 1990; Xu et al., 1991). Although the responses evoked from the grafted striatal cells resemble those evoked from the endogenous host medial spiny striatal neurons, some electrophysiological characteristics remain unique to grafted neurons.
Cell-based treatments of neurodegenerative diseases have been tested clinically with partial success. In the context of Huntington's disease (HD), experimental studies show that the grafted embryonic striatal cells survive, integrate within the host brain, and reverse some functional deficits. Importantly, once transplanted, the grafted striatal neurons retain a significant level of cellular, morphological, and functional plasticity which allows the experimental modification of their character through the manipulation of environmental cues or learning protocols. Using embryonic striatal grafts in the rodent model of HD as the principal example, this chapter summarizes seminal experiments that demonstrate that environmental factors, training, and activity can tap into mechanisms that influence the development of the grafted cells and can change the profile of graft-mediated behavioral recovery. Although currently there is limited understanding of the biological rationale behind the recovery, we put forward experimental data indicating that striatal grafts can express experience-dependent physiological plasticity at the synaptic as well as at the systemic functional level.
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Astrocytes, oligodendroglia, extracellular space volume and geometry in rat fetal brain grafts
1999, Neuroscience
Fetal neocortex or tectum transplanted to the midbrain or cortex of newborn rats develops various degrees of gliosis, i.e. increased numbers of hypertrophied, glial fibrillary acidic protein-positive astrocytes. In addition, there were patches or bundles of myelinated fibres positive for the oligodendrocyte and central myelin marker Rip, and increased levels of extracellular matrix molecules. Three diffusion parameters—extracellular space volume fraction α (α=extracellular volume/total tissue volume), tortuosity λ (λ= $D/ADC$ , where D is the free and ADC is the apparent tetramethylammonium diffusion coefficient) and non-specific uptake k′—were determined in vivo from extracellular concentration–time profiles of tetramethylammonium. Grafts were subsequently processed immunohistochemically to compare diffusion measurements with graft morphology. Comparisons were made between the diffusion parameters of host cortex and corpus callosum, fetal cortical or tectal tissue transplanted to host midbrain (“C- and T-grafts”) and fetal cortical tissue transplanted to host cortex (“cortex-to-cortex” or C-C-grafts). In host cortex, α ranged from 0.20±0.01 (layer V) to 0.21±0.01 (layers III, IV and VI) and λ from 1.59±0.03 (layer VI) to 1.64±0.02 (layer III) (mean±S.E.M., n=15). Much higher values were found in “young” C-grafts (81–150 days post-transplantation), where α=0.34±0.01 and λ=1.78±0.03 (n=13), as well as in T-grafts, where α=0.29±0.02 and λ=1.85±0.04 (n=7). Further analysis revealed that diffusion in grafts was anisotropic and more hindered than in host cortex. The heterogeneity of diffusion parameters correlated with the structural heterogeneity of the neuropil, with the highest values of α in gray matter and the highest values of λ in white matter bundles. Compared to “young” C-grafts, in “old” C-grafts (one year post-transplantation) both α and λ were significantly lower, and there was a clear decrease in glial fibrillary acidic protein immunoreactivity throughout the grafted tissue. In C-C-grafts, α and λ varied with the degree of graft incorporation into host tissue, but on average they were significantly lower (α=0.24±0.01 and λ=1.66±0.02, n=8) than in young C- and T-grafts. Well-incorporated grafts revealed less astrogliosis, and α and λ values were not significantly higher than those in normal host cortex.
The observed changes in extracellular space diffusion parameters could affect the movement and accumulation of neuroactive substances and thus impact upon neuron–glia communication, synaptic and extrasynaptic transmission in the grafts. The potential relevance of these observations to human neuropathological conditions associated with acute or chronic astrogliosis is considered.
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Regular ArticleEvidence for Enhanced Synaptic Excitation in Transplanted Neostriatal Neurons

Abstract

Regular Article
Evidence for Enhanced Synaptic Excitation in Transplanted Neostriatal Neurons