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内容記述 |
Precise synaptic connections and appropriate synaptic transmission are essential for proper functions of the brain. Both of which are established via the postnatal development and can be reorganized according to new environments. Lemniscal synapses in the ventroposterior medial (VPM) thalamic nucleus are afferent synapses, which convey somatosensory information from the trigeminal nuclei. Lemniscal synapses of the adult mice are characterized by the synaptic connections that a relay neuron receives one lemniscal fiber and by the fast reliable synaptic transmission. Such characteristics are established during the postnatal development. However, the entire functional development of lemniscal synapses remains unknown. Even after lemniscal
synapses become mature, functional remodeling, such as expansion and shrinking of receptive fields, in the somatosensory thalamus induced by the lesion of the peripheral sensory nerve has been described in in vivo. However, it is still unknown how lemniscal synapses change underlying the functional remodeling of the somatosensory thalamus. Thus, he investigated developmental changes and peripheral nerve injury-induced remodeling of lemniscal synapses using whole-cell patch-clamp technique in brain slice preparations of mice. His thesis is organized into three chapters. In the first chapter (chapter 1), he proposes three distinct stages of developmental changes at lemniscal synapses based on synaptic properties and innervation patterns of lemniscal fibers onto a relay neuron. His findings are as follows: (1) During the first stage (P0 - 6), the number of lemniscal fibers which innervate a relay neuron increases. The amplitude of total lemniscal EPSCs via both NMDA and AMPA receptors rapidly grows at the end of this stage. (2) During the second stage (P7 - 20), redundant lemniscal fibers are dramatically eliminated. As a result, a relay neuron becomes innervated by a single lemniscal fiber by P21. Silent lemniscal synapses, which are abundant during the first stage, disappear during this stage. The AMPAR/NMDAR ratio of EPSC gradually increases in a similar time course. Moreover, the decay time of AMPAR-mediated EPSCs becomes shorter during this stage. A switch of alternative splice variants of AMPA receptor subunits (from flip to flop) underlies the phenomenon. (3) During the third stage (P21~), all synaptic properties are stable, indicating that the development is already completed. In the second chapter (chapter 2), he reports the peripheral nerve cut-induced remodeling of mature lemniscal synapses. He cuts the infraorbital nerve (a part of maxillary nerve passing through infraorbital canal, which convey somatosensory information from maxillary region) of mice on P21. One week after the operation (IONC) on P21, multiple reinnervation of lemniscal fibers onto a relay neuron are observed. In addition, the IONC operation induces silent lemniscal synapses. The IONC operation decreases the amplitude of single fiber-mediated EPSCs, but not that of total lemniscal EPSCs of a given relay neuron. Multiply innervating lemniscal fibers are classified into two distinct populations; "Strong fibers" with shorter decay time and larger amplitude of AMPAR-mediated lemniscal EPSCs and "Weak fibers" with longer decay time and smaller amplitude. A cluster analysis and innervation patterns of the two types of fibers strongly suggest that Weak fibers are newly-recruited fibers. Moreover, current-voltage relationships and pharmacological analyses indicate that the IONC operation up-regulates GluR2-containing and flip-type AMPA receptors at the postsynaptic sites of Weak fibers. In contrast, no change is observed on NMDAR-mediated EPSCs. Paired-pulse ratio and coefficient of variation of AMPAR-mediated lemniscal EPSCs are elevated at Weak fiber synapses. These results suggest that the IONC operation can induce remodeling of lemniscal synapses even after the synapses become mature. Notably, because the whisker deprivation does not multiple reinnervation of lemniscal fibers onto a relay neuron, such reinnervation are likely caused by the injury of peripheral nerve rather than the lack of whisker mediated sensory inputs. In the third chapter (chapter 3), the similarity between the developing and remodeled (by peripheral nerve lesions or such) nervous systems is discussed. The present data on lemniscal synapses exhibited the similarity; the remodeled lemniscal fibers by the IONC operation showed immature properties, including the multiple innervation and the small AMPA/NMDA ratio of EPSCs. Previous studies have reported that the remodeling of other particular synapses after nerve lesions also results in showing immature synaptic properties. Thus, the remodeling toward immature phenotypes is presumably general after the adult nervous system undergoespathological conditions, which may suggest the recapitulation of the development. Although the normal development and the remodeling after pathological conditions would have different functional significance, they appear to share common neural mechanisms by which the nervous system actively reorganizes itself. |
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