Abstract
Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL). The expression of selected genes was assessed by quantitative real-time PCR in the hippocampal tissue at the injured side and the contralesional side at day 4 and 14 after injury. We observed that expression of genes coding for synaptotagmin 1, ezrin, thrombospondin 4, and C1q proteins, that have all been implicated in the synapse formation, re-arrangement and plasticity, were upregulated both in the injured and the contralesional hippocampus, implying a plasticity response in the uninjured hemisphere. Several of the genes, the expression of which was altered in response to ECL, are known to be expressed in astrocytes. To test whether astrocyte activation plays a role in the observed plasticity response to ECL, we took advantage of mice deficient in two intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP−/−Vim−/−) and exhibiting attenuated astrocyte activation and reactive gliosis. The absence of GFAP and vimentin reduced the ECL-induced upregulation of thrombospondin 4, indicating that this response to ECL depends on astrocyte activation and reactive gliosis. We conclude that even a very limited focal neurotrauma triggers a distinct response at the contralesional side, which at least to some extent depends on astrocyte activation.
Highlights
Experience-dependent adaptation and learning are at the structural level based on dendritic and axonal arborization, spine density, synapse number and size, receptor density and in some brain regions the generation of new neurons
To confirm that entorhinal cortex lesion (ECL) resulted in the expected indirect injury and astrocyte response in the hippocampus on the injured side, we first determined the mRNA levels of glial fibrillary acidic protein (GFAP) and vimentin (Vim), the increased expression of which is a hallmark of astrocyte activation
We observed that both at 4 and 14 days after ECL, GFAP and vimentin expression was significantly increased in the deafferented hippocampus (GFAP by 534% and 79%, respectively, and Vim by 558% and 82%, respectively)
Summary
Experience-dependent adaptation and learning are at the structural level based on dendritic and axonal arborization, spine density, synapse number and size, receptor density and in some brain regions the generation of new neurons. Together, these structural constituents of neural plasticity contribute to recovery of function after CNS injury [1]. Astrocytes play an important role in the regulation of several constituents of neural plasticity including cell genesis, control of the number of neuronal synapses and synapse function [1,9]. To elucidate the role of activated astrocytes in the contralesional response to ECL, we used mice with genetically ablated ability to express glial fibrillary acidic protein (GFAP) and vimentin, two intermediate filament (nanofilament) proteins, the upregulation of which is a hallmark of astrocyte activation in response to CNS injury [7,14,17,18]
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