Not Committing Barbarisms: Sherrington and the Synapse, 1897

The word synapse first appeared in 1897, in the seventh edition of Michael Foster’s Textbook of Physiology. Foster was assisted in writing the volume on the nervous system by Charles Sherrington, who can be credited with developing and advocating the physiological concept of a synapse. The word itself however, was derived by a Cambridge classicist, Arthur Verrall.     

Ultrastructural features of synapse from dorsal parvocellular reticular formation neurons to hypoglossal motoneurons of the rat

The dorsal parvocellular reticular formation (PCRt) receives projection of the trigeminal mesencephalic nucleus neurons. It contains the dorsal group of interneurons that integrate and coordinate activity of the oral motor nuclei. Ultrastructural features of synaptic connection from the dorsal PCRt neurons to the motoneurons of the hypoglossal nucleus (XII) were examined at both the light and electron microscopic levels in rats. Biotinylated dextran amine (BDA) was initially iontophoresed into the dorsal part of PCRt unilaterally. Seven days later horseradish peroxidase (HRP) was injected into the body of the tongue. After histochemical reaction for visualization of HRP and BDA, the BDA-labeled fibers and terminals were seen distributing bilaterally in XII with ipsilateral predominance. BDA-labeled terminals were closely apposed upon HRP retrogradely labeled somata and dendrites of the XII motoneurons. A total of 1408 BDA-labeled boutons were examined ultrastructurally, which had mean size of 1.22+/-0.37 microm in diameter. Five hundred-ninety three of these boutons in both the ipsilateral (n=401) and contralateral (n=192) XII were seen to synapse on both the dendrites and somata of HRP-labeled motoneurons. The vast majorities of synapses were axodendritic (98%, 580/593), while 2% of them were axosomatic. Of the 1408 BDA-labeled boutons, 69.6% of them were S-type boutons containing small clear and spherical synaptic vesicles and 30.4% of them were PF-type boutons containing pleomorphic and flattened synaptic vesicles. Approximately 64% of synapses between BDA-labeled boutons and HRP-labeled motoneurons were asymmetric, and 33% of synapses were symmetric. No axoaxodendritic or axoaxosomatic synaptic triad was observed. The present study illustrated the anatomical pathway and synaptological characteristics of neuronal connection between the dorsal PCRt premotor neurons and the XII motoneurons. Its functional significance in coordinating activity of XII motoneurons during oral motor behaviors has been discussed.     

Fundamental aspects of the developing brain: synapse formation

The phenomena presiding over synaptogenesis in the developing brain, notably death of neurons and the nerve growth factor are described as well as the neurobiological and ultrastructural features of synapse maturation. Synapse and connection specificity in the brain versus plasticity are given consideration. Infantile neuroaxonal dystrophy is suggested as a possible example of defective synaptogenesis.     

Recycling and EH domain proteins at the synapse

In neurons, a network of endocytic proteins accomplishes highly regulated processes such as synaptic vesicle cycling and the timely internalization of intracellular signaling molecules. In this review, we discuss recent advances on molecular networks created through interactions between proteins bearing the Eps15 homology (EH) domain and partner proteins containing the Asn–Pro–Phe (NPF) motif, which participate in important aspects of neuronal function as the synaptic vesicle cycle, the internalization of nerve growth factor (NGF), the determination of neuronal cell fate, the development of synapses and the trafficking of postsynaptic receptors. We discuss novel functional findings on the role of intersectin and synaptojanin and then we focus on the features of an emerging family of EH domain proteins termed EHDs (EH domain proteins), which are important for endocytic recycling of membrane proteins.     

The great deceiver: the role of convulsive syncope in the history of epilepsy

Because of its high medical and social profile, epilepsy has a voluminous documented history. For centuries it has been the subject of much speculation and attempted explanation. Even from antiquity examples taken from every day life have been used to explore, by analogy, the mechanism of epileptic seizures; and the convulsive phenomena of acute exsanguination have attracted much attention for this reason. A survey of the aspects and the consequences of this exercise in the study of seizure mechanisms shows that, until Jackson and Gowers emphasised the central role of the cortex in human epilepsy, a very complex schema had been constructed to explain epilepsy. This had been based upon erroneous information obtained by analogy from the convulsive phenomena of syncope and exsanguination. Over the millennia this mistaken concept served to divert scientific endeavour in attempts to explain and unravel the bases of epilepsy. It was only little more than a century ago that this concept was finally abandoned.     

MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction

Synapse elimination at the developing neuromuscular junction (NMJ) sculpts motor circuits, and synapse loss at the aging NMJ drives motor impairments that are a major cause of loss of independence in the elderly. Here we provide evidence that at the NMJ, both developmental synapse elimination and aging-related synapse loss are promoted by specific immune proteins, members of the major histocompatibility complex class I (MHCI). MHCI is expressed at the developing NMJ, and three different methods of reducing MHCI function all disrupt synapse elimination during the second postnatal week, leaving some muscle fibers multiply-innervated, despite otherwise outwardly normal synapse formation and maturation. Conversely, overexpressing MHCI modestly accelerates developmental synapse elimination. MHCI levels at the NMJ rise with aging, and reducing MHCI levels ameliorates muscle denervation in aged mice. These findings identify an unexpected role for MHCI in the elimination of neuromuscular synapses during development, and indicate that reducing MHCI levels can preserve youthful innervation of aging muscle.     

The history of the golgi apparatus in neurones from its discovery in 1898 to electron microscopy

We celebrate in 1998 the centenary of the discovery of the Golgi apparatus. Neurones have played a special role in the history of this cell organelle, primarily because the endocellular apparatus was discovered in nerve cells by Camillo Golgi when he was studying the cerebellum of an owl. In the following years, the apparatus of the nerve cell represented the prototype of this cell component which, however, was soon also detected in many other cell types. During the 1920s and 1930s the original idea of a Golgi endocellular “network” was refused and research was focused on the constituents and function of the organelle, using various tissues and techniques. However, the real existence of the apparatus was seriously questioned until the organelle was finally identified by electron microscopy in the mid-1950s. The studies performed on nerve cells during these decades is briefly reviewed here.     

Increased immunoreactivity of brain spectrin in Alzheimer disease: a marker for synapse loss?

Alzheimer disease (AD) is characterized, among other pathological alterations, by an extensive synapse loss. Brain spectrin is a membrane skeleton protein found in synapses, and its immunoreactivity has been shown to increase in the rat model of denervation. In order to test the hypothesis that there is an increase in brain spectrin immunoreactivity in relation to the synapse pathology in AD, we studied brain sections and homogenates from AD and control cases and found increased anti-brain spectrin immunostaining of neurons, fibers, and plaques, with a relative decrease in the granular pattern of neuropil immunoreactivity. Western blot analysis showed a 25% increase in the 150 kDa bands (degradation products) in the cytosolic fraction and a decrease in the 240 kDa band (intact brain spectrin) in the particulate fraction. Altered immunostaining of brain sections and Western blot was not observed with an antibody against red blood cell spectrin demonstrating the specific change of brain spectrin. These results support the contention that increased brain spectrin immunoreactivity is a marker of synapse or neuronal loss and further supports the concept of synapse pathology in AD.     

The history of thought concerning the hypothalamus and its functions

Many initial studies related to identification of the boundaries and structural components, nuclei, tracts and interconnections of the hypothalamus, this continues. Early interest also focused on hypothalamic control of somatic activities and autonomie nervous system functions. During the present century chiefly, interest has developed in the hypothalamus and control of water balance, thirst, water retention and loss (diabetes insipidus and polydipsia). Its role in control of metabolism, body weight (obesity), and the regulation of body temperature has attracted the attention of physiologists for many years. Others have studied hypothalamic regulation of sex and reproductive phenomena. The hypothalamus is now attracting much attention because of its production of neuroendocrine secretions and role in control of the endocrine system. Physiologists realized very early that the hypothalamus is involved in emotional expression, in reaction to stress and adaptive adjustments. Its involvement in disease states and resistance thereto and in determining the nature of behavior has now been recognized as a matter of great importance. The origins of all these interests are reviewed.     

Synapse selection based on differences in synapse turnover

Rat retinal neurons formed transient synapses with rat muscle cells in culture only during a discrete period in development, from the 20th day of embryonic development to the 7th neonatal day. In contrast, chick embryo spinal cord neurons formed synapses at all developmental stages tested, from the 2nd to the 18th day of embryonic development. The percentage of cells from the spinal cord that formed synapses with muscle cells was maximum at 4 days of embryonic development and decreased thereafter. However, the number of synapses with muscle formed by cells from 8-day embryonic spinal cord did not decrease during 14 days of culture. Under identical conditions, all synapses formed between rat retinal neurons and muscle cells were terminated during 7 days of culture. These results show that differences in the rates of turnover of two populations of cholinergic synapses can result in the selective retention of one population of synapses and the loss of the other, and thereby alter the specificity of synaptic connections.     

Rab3A deletion selectively reduces spontaneous neurotransmitter release at the mouse neuromuscular synapse

Rab3A is a synaptic vesicle-associated GTP-binding protein thought to be involved in modulation of presynaptic transmitter release through regulation of vesicle trafficking and membrane fusion. Electrophysiological studies at central nervous system synapses of Rab3A null-mutant mice have indicated that nerve stimulation-evoked transmitter release and its short- and long-term modulation are partly dependent on Rab3A, whereas spontaneous uniquantal release is completely independent of it. Here, we studied the acetylcholine (ACh) release at the neuromuscular junction (NMJ) of diaphragm and soleus muscles from Rab3A-deficient mice with intracellular microelectrode methods. Surprisingly, we found 20-40% reduction of spontaneous ACh release but completely intact nerve action potential-evoked release at both high- and low-rate stimulation and during recovery from intense release. The ACh release induced by hypertonic medium was also unchanged, indicating that the pool of vesicles for immediate release is unaltered at the Rab3A-deficient NMJ. These results indicate a selective role of Rab3A in spontaneous transmitter release at the NMJ which cannot or only partly be taken over by the closely related Rab3B, Rab3C, or Rab3D isoforms when Rab3A is deleted. It has been hypothesized that Rab3A mutation underlies human presynaptic myasthenic syndromes, in which severely reduced nerve action potential-evoked ACh release at the NMJ causes paralysis. Our observation that Rab3A deletion does not reduce evoked ACh release at any stimulation rate at the mouse NMJ, argues against this hypothesis.     

The history of status epilepticus and its treatment

Despite the fact that status epilepticus was been recognized since antiquity, its existence was largely ignored until the mid-nineteenth century. In this review we cover the medical literature of status epilepticus from the late nineteenth century until the early 1970s when the modern era of status epilepticus began. We pay particular attention to the impact of the ILAE and its principal members on the understanding and awareness of status epilepticus. We also cover the evolution of treatment regimens advocated for status epilepticus from the late nineteenth century to the early 1970s when the benzodiazepines were established as first line treatments.     

The early history (1909-1961) of Epilepsia, the journal of the International League Against Epilepsy, and its echoes today

Summary:  This paper records the history of Epilepsia , the journal of the International League Against Epilepsy, from its inception in 1908/1909 until the beginning of its fourth series in 1961. During this time, publication was interrupted on three occasions and so the journal appeared in four series, with a complex numbering system. Over the years, the content and format of the journal has varied. Its role has changed over the years, at times primarily as a scientific organ and at other times as a source of ILAE news and reports. Concerns throughout its history have included its role as an historical record, its international representation, financial vicissitude, quality of papers, the balance between basic and clinical science, the value of clinical papers, and issues of overspecialization. Epilepsia is today the leading clinical epilepsy journal; but these are still significant concerns, and a knowledge of the history of Epilepsia is important for understanding the current position of the journal.     

Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice

Tauopathies differ in terms of the brain regions that are affected. In Alzheimer's disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (>14 months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[(18)F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex-nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration.     

Differential development of Ca dynamics in presynaptic terminal and postsynaptic neuron of the rat auditory synapse

Postnatal development of Ca²⁺ influx and Ca²⁺ clearance capacity were investigated in the synapse of medial nucleus of the trapezoid body (MNTB) of rat with fura-2 fluorimetry. In contrast to the presynaptic terminal, Ca²⁺ dynamics does not basically change in the postsynaptic principal neuron developmentally. This differential development of Ca²⁺ dynamics between pre- and postsynaptic neurons might be crucial for the organized formation and functional maturation of this synapse.