Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

GluR2/3受体在不同年龄大鼠背侧蜗神经核的表达

目的研究α-氨基羟甲基恶唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid,AMPA)受体亚型GluR2/3(Glutamate recptor 2/3)在不同周龄大鼠蜗神经核的表达。方法用免疫组化方法检测GluR2/3亚型在不同年龄(1～16周)SD大鼠(Sprague-Dawlay rat)背侧蜗神经核中的表达,免疫电镜技术检测其在细胞内的定位。结果1周龄大鼠蜗神经核中无明显表达,2周时开始出现该受体的表达,3周时亦有极少量表达,4周时表达有明显增加,以后依次递增,至9周时表达最强,以后逐渐下降,并稳定于16周。各周龄受体均表达于包膜及胞浆中。电镜下(6周、10周)时见胶体金主要沉积于线粒体,部分可见于粗面内质网及胞浆。结论出生后GluR2/3在蜗神经核的含量随年龄变化而变化,这种改变可能与听觉发育及可塑性相关。     

Subsurface and cytoplasmic cisterns associated with mitochondria in pyramidal neurons of the rat dorsal cochlear nucleus

Pyramidal cells, the principal neurons of the dorsal cochlear nucleus in the rat, have a system of hypolemmal cisterns as prominent as that of cerebellar Purkinje cells. In their perikarya nearly all the subsurface cisterns are closely apposed to mitochondria as in Purkinje cells. This feature emphasizes a similarity between the two types of neuron which both have dendrites residing in the molecular layer. In addition, cochlear pyramidal neurons contain a distinct cytoplasmic cysternal core which includes cisternae with narrow lumina. These occasionally form simple and multiple assemblies with mitochondria.     

Selective vulnerability of adult cochlear nucleus neurons to de-afferentation by mechanical compression

It is well established that the cochlear nucleus (CN) of developing species is susceptible to loss of synaptic connections from the auditory periphery. Less information is known about how de-afferentation affects the adult auditory system. We investigated the effects of de-afferentation to the adult CN by mechanical compression. This experimental model is quantifiable and highly reproducible. Five weeks after mechanical compression to the axons of the auditory neurons, the total number of neurons in the CN was evaluated using un-biased stereological methods. A region-specific degeneration of neurons in the dorsal cochlear nucleus (DCN) and posteroventral cochlear nucleus (PVCN) by 50% was found. Degeneration of neurons in the anteroventral cochlear nucleus (AVCN) was not found. An imbalance between excitatory and inhibitory synaptic transmission after de-afferentation may have played a crucial role in the development of neuronal cell demise in the CN. The occurrence of a region-specific loss of adult CN neurons illustrates the importance of evaluating all regions of the CN to investigate the effects of de-afferentation. Thus, this experimental model may be promising to obtain not only the basic knowledge on auditory nerve/CN degeneration but also the information relevant to the application of cochlear or auditory brainstem implants.     

Corticofugal actions on the lateral cervical nucleus of the cat

The question of possible corticofugal actions on the lateral cervical nucleus (LCN) of the cat was reinvestigated. Recordings were made from single relay cells, identified histologically as lying in the LCN which was deafferented by spinal cord lesions to avoid interference from corticospinal-cervical pathways. Intracortical stimulation of the contralateral sensorimotor cortex inhibited all 53 cells studied, but in addition excited only 25% of them (mean latency 5 ms). Cortical stimulation also inhibited mass transmission through the LCN. Care was taken to avoid inhibition due to stimulating high-threshold receptors in the head. Exploration with the stimulating electrode of large parts of the cerebral cortex allowed lowest threshold (45 to 90 μA; 10 ms train of cortical shocks of 1 ms duration at 500 Hz) zones for inhibition of the LCN to be located, but no low-threshold zones for excitation could be found. (Indirect current spread with such stimulation of the cortex was shown to be about 1.5 mm.) Histological reconstruction of the stimulating tracks showed that the low-threshold zone was cylindrical, rostrally, lying in the grey matter of that part of the cytoarchitectural area 3a which represents the face. Caudally, the low-threshold zone was in white matter where the corticofugal pathway would be expected to course. Such a nonsomatotopically organized inhibitory pathway is unusual in sensory systems and suggests that the LCN may be involved in certain tasks requiring face-limb coordination.     

Optic nystagmus and vestibular nuclei: Unitary activity of vestibular neurons during nystagmus

The behavior of 102 vestibular neurons during optic nystagmus was investigated in 25 guinea pigs with extracellular microelectrodes. The recorded vestibular neurons were electrophysiologically identified by their orthodromic response to ipsilateral labyrinthine stimulation and by antidromic activation from the medial longitudinal fascicle. Of the 102 recorded units, 92 were modulated by the electrical stimulation of at least one optic nerve. The presence of vestibular neurons sensitive to the direction of nystagmus induced by labyrinthine or optic stimulation was also analyzed.     

Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function

Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain’s glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.     

An electron microscopic study of the corticorubral fibers after neonatal deep cerebellar nuclear lesions in albino rats

After a lesion in the sensorimotor and adjacent cortex in normal adult rats, degenerating terminals showing the dense reaction form asymmetrical contacts with spines, dendrites of various sizes, soma and other axonal terminals. Filamentous degeneration is also present. After neonatal deep cerebellar nuclear lesions involving the dentate nucleus and the adjacent interposed nucleus, the cerebrocorticorubral fibers form similar synaptic contacts with somatic, dendritic and axonal profiles. The incidence of axo-dendritic contacts on spine is reduced, while that of axo-dendritic contacts on small, medium-sized and large dendrites and axo-somatic contacts is increased.     

The common organization of the amygdaloid complex in tetrapods: new concepts based on developmental, hodological and neurochemical data in anuran amphibians

Research over the last few years has demonstrated that the amygdaloid complex in amniotes shares basic developmental, hodological and neurochemical features. Furthermore, homolog territories of all main amygdaloid subdivisions have been recognized among amniotes, primarily highlighted by the common expression patterns for numerous developmental genes. With the achievement of new technical approaches, the study of the precise neuroanatomy of the telencephalon of the anuran amphibians has been possible, revealing that most of the structures present in amniotes are recognizable in these anamniotes. Thus, recent investigations have yielded enough results to support the notion that the organization of the anuran amygdaloid complex includes subdivisions with origin in ventral pallial and subpallial territories, a strong relationship with the vomeronasal and olfactory systems, abundant intra-amygdaloid connections, a main output center involved in the autonomic system, profuse amygdaloid fiber systems, and distinct chemoarchitecture. When all these new data about the development, connectivity and neurochemistry of the amygdaloid complex in anurans are taken into account, it becomes patent that a basic organization pattern is shared by both amniotic and anamniotic tetrapods.     

Anatomical projections of the nuclei of the lateral lemniscus in the albino rat (rattus norvegicus)

The ascending projections to the lateral lemniscal nuclei and the inferior colliculus were investigated in the albino rat by using Fluoro‐Gold, either alone or in combination with other retrograde tract tracers. Injections were made into the central nucleus of the inferior colliculus (ICC), the dorsal nucleus of the lateral lemniscus (DNLL), the intermediate nucleus of the lateral lemniscus (INLL), or the ventral nucleus of the lateral lemniscus (VNLL). The ICC receives both ipsilateral and contralateral projections from the DNLL and the lateral superior olive, major ipsilateral projections from the INLL, VNLL, medial superior olive, and superior paraolivary nucleus, and major contralateral projections from both dorsal and ventral cochlear nucleus. The DNLL receives a similar pattern of projections from the auditory lower brainstem nuclei. The INLL, in contrast, receives its major projections from the ipsilateral VNLL, lateral superior olive, medial superior olive, superior paraolivary nucleus, and medial nucleus of the trapezoid body, but does not receive a heavy projection from the contralateral lateral superior olive. It receives a major contralateral projection from the ventral cochlear nucleus, but a much lighter projection from the contralateral dorsal cochlear nucleus. The VNLL receives projections from the ipsilateral medial nucleus of the trapezoid body and the contralateral ventral cochlear nucleus, but does not receive projections from the medial or lateral superior olives, the superior paraolivary nucleus, or the dorsal cochlear nucleus. Thus, the three primary subdivisions of the rat's lateral lemniscus can be distinguished from each other on the basis of their distinctive projection patterns. J. Comp. Neurol. 512:573–593, 2009. © 2008 Wiley‐Liss, Inc.