Dendritic spine "dysgenesis" and mental retardation.

Golgi studies reveal abnormally long, thin spines and the absence of short, thick spines on dendrites of cortical neurons in retarded children with normal karyotypes. The degree of dendritic spine loss and abnormality appears to be related to age and the severity of developmental retardation. Dendritic spine "dysgenesis" is a common feature of the microstructural pathology that occurs in profound mental retardation of unknown etiology.

Autism and mental retardation: neuropathologic studies performed in four retarded persons with autistic behavior.

Four persons who exhibited prominent autistic features throughout life died when 4, 14, 27, and 33 years old. All were mentally retarded. One had documented phenylketonuria, but the cause of mental retardation and autistic behavior was undefined in three. At the time of autopsy, brain weights were within 2 SDs of the norm for age. Complete neuropathologic examination, including analysis of cortical neurons impregnated with the rapid Golgi method, failed to provide clues as to cause or the pathoanatomic substrate of autistic behavior in these cases.

Evidence for autapses in the substantia nigra.

Intracellular recording and intracellular HRP staining were employed to trace the recurrent terminal plexus of cat substantia nigra pars reticulata neurons. Autaptic neurons were labeled. The axon of an autaptic neuron was found to emit a recurrent collateral which distributed 'en passage' and terminal boutons contacting dendrites of the parent cell. Antidromic ventromedial thalamic stimulation elicited a recurrent IPSP in the autaptic neuron.

Meganeurites and other aberrant processes of neurons in feline GM1-gangliosidosis: a Golgi study.

Golgi studies were carried out on neurons in several forebrain structures of young adult mutant cats with inherited beta-galactosidase deficiency and neurobehavioral deterioration due to GM1-ganglioside storage disease. Meganeurites similar to those observed in several human gangliosidoses were present on small and medium pyramidal neurons, granule cells of the fascia dentata and spiny neurons of the caudate nucleus. Large and giant pyramidal cells of the motor cortex exhibited prominent somatic spines but lacked meganeurites. Cortical non-pyramidal neurons and aspiny caudate cells were relatively normal in appearance although they showed variable increases in cell body diameter. The range of morphological alterations in different types of cortical neurons in feline GM1-gangliosidosis was identical to that found in human ganglioside storage diseases. Neurite outgrowth from meganeurites was particularly prominent in the feline mutant. The extensive proliferation of neurites confined to meganeurites indicates that the latter have growth properties typical of embryonic neuronal elements. The demonstration of neurite outgrowth from meganeurites of mature cortical neurons in feline GM1-gangliosidosis suggests a possible role for gangliosides in neurite formation during neuronal differentiation and synaptogenesis.

Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease.

Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

Ultrastructure of neurites and meganeurites of cortical pyramidal neurons in feline gangliosidosis as revealed by the combined Golgi-EM technique.

Application of the Golgi-EM technique to the study of altered cortical pyramidal neuron morphology in feline gangliosidosis has revealed the presence of aberrant synapses in relation to multiple neurites and secondary neurites of meganeurites. In addition fine neurites arising from the soma and meganeurite are found to project into and envelope elements of the surrounding neuropil. These observations provide further evidence for a disturbance in neuronal surface membrane regulation in ganglioside storage disease.

Microtubule disarray in cortical dendrites and neurobehavioral failure. I. Golgi and electron microscopic studies.

Cortical biopsies obtained from 5 young children with severe neurobehavioral retardation of unknown etiology have been analyzed using Golgi and EM techniques. The normally cylindrical geometry of individual dendritic processes of pyramidal and non-pyramidal neurons is interrupted by the formation of distinct varicosities. While over 90% of observed cells are affected, the extent of varicosity formation varies from cell to cell and is most prominent in medium and small pyramidal cells. Varicosities may occur in the periphery only, or they may extend proximally to primary dendritic trunks. Accompanying changes include thin and irregular proximal processes, loss of dendritic spines, and predominance of long, thin tortuous spines. Ultrastructural analysis reveals characteristic changes in the cytoskeleton of these processes. Microtubules, within the larger proximal processes, twist and turn, relative to one another and relative to the long axis of the process. In varicose regions, microtubules course in roughly parallel array through constricted segments, only to splay away from one another on entering an expansion. Synapses are evident on constricted and expanded segments, as well as on spines. Alterations in dendritic structure of both pyramidal and non-pyramidal neurons may represent a primary target in the pathobiological process underlying neurobehavioral failure.

Microtubular disarray in cortical dendrites and neurobehavioral failure. II. Computer reconstruction of perturbed microtubular arrays.

A previous report details morphological alterations in dendritic structure of cortical neurons in severe neurobehavioral retardation of unknown etiology. Using computer graphic techniques, the present study describes perturbations in the 3-dimensional character of the microtubular array, which correspond to degenerative change in dendritic geometry. In large proximal processes, two types of array have been reconstructed. Segmented microtubules may form a continuous helical swirl which underlies a bulge in the dendritic cylinder. Alternatively, small groups of microtubules, while maintaining orderly internal organization, may be disoriented with respect to the long axis of the process. In varicose regions of the dendrite the microtubular array is discontinuous. Microtubules course side by side through constructed regions, only to splay out and terminate within expanded regions. These pathological alterations in the microtubular array contrast sharply with the cortical dendritic microtubular array reconstructed from the normal adult mouse. Perturbation in those parameters which determine packing of microtubules within the dendritic process is also documented. In the pathological condition, microtubules lose the ability to exclude one another from close approach. The role of cross-linking molecules in maintaining the integrity of the microtubular array, and the role of microtubules in maintaining the geometry of the dendrite, are considered.

Fine structure of meganeurites and secondary growth processes in feline GM1-gangliosidosis.

Electron microscope studies were carried out on neurons of the hippocampal formation in a feline mutant with beta-galactosidase deficiency and GMI-gangliosidosis. Fusiform processes with characteristics similar to meganeurites of Golgi studies were identified between cell bodies and axons of pyramidal and granule cells. The presence of dense material subjacent to the plasma membrane at the meganeurite-axon junction provides evidence that meganeurites form at the axon-hillock region and displace the initial axonal segment distally. Meganeurites of hippocampal neurons exhibited pleomorphic secondary processes with fine structural features of growth cones. Spines and spine-synapses were abundant on perikarya and meganeurites. Numerous membranous cytoplasmic bodies (MCBs) were encountered amongst otherwise normally appearing organelles of the cell body. MCBs were densely packed in meganeurites except near their peripheral area. They were less common in dendrites and rare in synapses of the neuropil. The observations provide further support for the view that meganeurites of mature cortical neurons in ganglioside storage diseases have embryonic growth characteristics.

Morphology and fine structure of the feline neonatal medullary raphe nuclei.

A light and electron microscopic study of the caudal medullary raphe nuclei of neonatal kittens reveals that these nuclei are composed of three size classes of neurons with several possible subclasses. Internuclearly projecting dendritic arborizations in the transverse plane and intranuclear projections in the sagittal plane are common features of large and medium size class neurons of raphe nuclei magnus and obscurus though not for the cells of nucleus raphe pallidus. A positive correlation exists between neuron size and density of axosomatic and axodendritic synapses, which suggests that the large class neurons are the first to receive input in synaptogenesis, which is occurring at this time. A wide variety of synaptic forms and integration is also a characteristic feature within these nuclei, though it is not clear whether this morphological variance represents a phylogenic and/or ontogenic trend or just an expression of the multifunctional nature of this region.

Fine structure of growth cones in medullary raphe nuclei in the postnatal cat.

Morphological aspects of the dynamic processes of growth cone formation and synaptogenesis have been studied in neonatal kitten (2-17 days) medullary raphe nuclei. The formation and elaboration of dendritic growth cones and primary dendritic trunks is actively taking place on the medium size class neurons (stellates) of these nuclei. The dendritic growth cones are morphologically distinctive due to their population of large dense-core vesicles and postsynaptic position. Another growth cone morphology, interpreted as axonal, is also described. This growth cone is typically found in close association or synaptic contact with the dendritic growth cones and contains, in addition to synaptic vesicles, a dense-core vesicle population distinguishable from that of the dendritic growth cone by the presence of a variety of vesicles containing an eccentrically positioned dense particle. No evidence of axo-axonic or dendrodendritic synapses has been found. Synaptogenesis was found to be occurring on somas, dendrites and dendritic growth cones throughout the medullary raphe nuclei, though this phenomenon was more apparent in indistinctly localized subnuclear spaces termed synaptogenic zones. Within these zones large class neurons are found to have greater densities of both axodendritic and axosomatic synapses than medium and small class neurons respectively. Axodendritic synaptic densities on primary and secondary dendrites of large and medium class neurons are greater than their respective axosomatic synapse densities, which may suggest that the latter forms at a later period of development.