Functional variability of sacral roots in bladder control.

OBJECT: Sacral roots are involved in sensory, autonomic, and motor innervation of the lower limbs and perineum. Theoretically, it can be assumed that the S-3 root level innervates the bladder; however, clinical practice shows that this distribution can vary. Few researchers have studied this variability. METHODS: The authors conducted a retrospective study involving 40 patients who underwent surgery requiring an electrophysiological exploration of the sacral roots. They performed stimulations for the monitoring of muscular (3 Hz, 1 V) and bladder responses under cystomanometry (30 Hz, 10 V). RESULTS: Although the S-3 roots were involved in bladder innervation in all cases, they were exclusively involved (i.e., the only nerve roots involved) in only 8 of 40 cases. In the remaining 32 cases, other sacral nerve roots were involved. The most common association was S-3+S-4 (12 cases), followed by S-2+S-3 (6 cases), S-2+S-3+S-4 (5 cases), and S-3+S-4+S-5 (2 cases). Stimulation of S-2 could sometimes induce bladder contraction (15 cases, 40%); however, the amplitude was often low. S-4 nerve roots were involved in 24 of 40 cases (60%) in the bladder motor function, whereas S-5 roots were only involved 7 times (17%). Occasionally, we noticed a horizontal asymmetry in the response, with a predominant response from the right side in 6 of 7 cases, always with a major S-3 response. CONCLUSIONS: This is the first study showing a significant horizontal and vertical variability in the functional distribution of sacral roots in bladder innervation. These results show the variability of cauda equina syndromes and their forensic implications. These data should help with the monitoring of sacral roots and the performance of several tasks during surgery, including neurostimulation and neuromodulation.

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice.

The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent microPET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.

Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders.

Multiple types of indirect evidence have been used to support theories of altered cortical connectivity in autism spectrum disorders (ASD). In other developmental disorders reduced spine expression is commonly found, while conditions such as fragile X syndrome show increased spine densities. Despite its relevance to theories of altered cortical connectivity, synaptic spine expression has not been systematically explored in ASD. Here we examine dendritic spines on Golgi-impregnated cortical pyramidal cells in the cortex of ASD subjects and age-matched control cases. Pyramidal cells were studied within both the superficial and deep cortical layers of frontal, temporal, and parietal lobe regions. Relative to controls, spine densities were greater in ASD subjects. In analyses restricted to the apical dendrites of pyramidal cells, greater spine densities were found predominantly within layer II of each cortical location and within layer V of the temporal lobe. High spine densities were associated with decreased brain weights and were most commonly found in ASD subjects with lower levels of cognitive functioning. Greater spine densities in ASD subjects provide structural support for recent suggestions of connectional changes within the cerebral cortex that may result in altered cortical computations.

Unidirectional startle responses and disrupted left-right co-ordination of motor behaviors in robo3 mutant zebrafish.

The Roundabout (Robo) family of receptors and their Slit ligands play well-established roles in axonal guidance, including in humans where horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by mutations in the robo3 gene. Although significant progress has been made toward understanding the mechanism by which Robo receptors establish commissural projections in the central nervous system, less is known about how these projections contribute to neural circuits mediating behavior. In this study, we report cloning of the zebrafish behavioral mutant twitch twice and show that twitch twice encodes robo3. We show that in mutant hindbrains the axons of an identified pair of neurons, the Mauthner cells, fail to cross the midline. The Mauthner neurons are essential for the startle response, and in twitch twice/robo3 mutants misguidance of the Mauthner axons results in a unidirectional startle response. Moreover, we show that twitch twice mutants exhibit normal visual acuity but display defects in horizontal eye movements, suggesting a specific and critical role for twitch twice/robo3 in sensory-guided behavior.

The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics.

To discover new genes involved in axon navigation, we conducted a forward genetic screen for recessive alleles affecting motor neuron pathfinding in GFP reporter mice mutagenized with ENU. In Magellan mutant embryos, motor axons were error prone and wandered inefficiently at choice points within embryos, but paradoxically responded to guidance cues with normal sensitivity in vitro. We mapped the Magellan mutation to the Phr1 gene encoding a large multidomain E3 ubiquitin ligase. Phr1 is associated with the microtubule cytoskeleton within neurons and selectively localizes to axons but is excluded from growth cones. Motor and sensory neurons from Magellan mutants display abnormal morphologies due to a breakdown in the polarized distribution of components that segregate between axons and growth cones. The Magellan phenotype can be reversed by stabilizing microtubules with taxol or inhibiting p38MAPK activity. Thus, efficacious pathfinding requires Phr1 activity for coordinating the cytoskeletal organization that distinguishes axons from growth cones.

Early motor development is abnormal in complexin 1 knockout mice.

Complexin I expression is dysregulated in a number of neurological diseases including schizophrenia and depression. Adult complexin 1 knockout (Cplx1(-/-)) mice are severely ataxic and show deficits in exploration and emotional reactivity. Here, we evaluated early behavioural development of Cplx1(-/-) mice. Cplx1(-/-) mice showed marked abnormalities. They develop ataxia by post-natal day 7 (P7), and by P21 show marked deficits in tasks requiring postural skills and complex movement. These deficits are consistent with abnormalities in sensory and motor development found in infants that develop schizophrenia in later life. A role for complexin I depletion should be considered in diseases where deficits in early sensory and motor development exist, such as autism and schizophrenia.

Spinal muscular atrophy: a delayed development hypothesis.

Spinal muscular atrophy is an inherited neuromuscular disorder. The gene responsible for the disease has been identified and named the SMN gene. This review is prompted by recent advances in understanding cellular function of the SMN gene and its gene product and by the increasing evidence that maturation of all parts of the neuromuscular system is delayed in spinal muscular atrophy patients. We suggest that the timing of developmental changes in motoneurons and muscles is critical for their survival. Delayed maturation of either motoneuron or muscle can cause these cells to die so the molecules that are involved in controlling their rate of maturation are crucial for normal development. We suggest that SMN gene/protein is one such molecule, because the neuromuscular system develops more slowly in spinal muscular atrophy patients, where SMN protein is absent, and in animals models, where SMN protein is reduced.

Patterning of the lateral ganglionic eminence by the Gsh1 and Gsh2 homeobox genes regulates striatal and olfactory bulb histogenesis and the growth of axons through the basal ganglia.

The function of the Gsh1 and Gsh2 homeobox transcription factors during development of the mouse telencephalon was studied using loss of function mutations. No telencephalic phenotype was observed in Gsh1 mutants, whereas Gsh2 and Gsh1/2 mutants showed progressively more severe defects in development of neurons derived from the lateral ganglionic eminence (LGE). These defects arise from abnormal dorsoventral specification of LGE progenitor cells. Mice lacking both Gsh1 and Gsh2 have severe hypoplasia of the striatum, olfactory tubercle, and interneurons that migrate from the dorsal LGE to the olfactory bulb. In addition, Gsh function is linked to the development of telencephalic dopaminergic neurons. These observations show that Gsh1 and Gsh2 have early roles in defining the identity of LGE progenitor cells. As a result of the basal ganglia defects in the Gsh1/2 mutants, there are pallial heterotopia near the cortical/subcortical limit and defects in the pathfinding of corticofugal and thalamocortical fibers. These findings highlight the developmental interdependence of adjacent telencephalic structures.

Retarded myelination in the lumbar spinal cord of piglets born with spread-leg syndrome.

Piglets born with spread-leg syndrome, a congenital weakness of the hindlimb adductors, were investigated to determine the site of lesion leading to limb impairment. Histological and immunohistochemical studies of the motor neuron unit showed no alterations but quantitative analysis revealed a reduction of axonal diameter and myelin sheath-thickness of the fibres innervating the adductors of the affected limbs. In the lumbar spinal cord a lack of myelination was observed in the tracts descending to the lower motor neurons. Recovery from the syndrome was accompanied by a catching-up of myelination with that of the controls. The spread-leg syndrome is due to a nutritional deficiency in the sow; thus it is assumed that the deficient maternal substances, mainly choline and methionine, are essential for the normal myelin production by spinal white matter oligodendrocytes of the fetus.

Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth.

Ciliary neurotrophic factor (CNTF) supports motor neuron survival in vitro and in mouse models of motor neuron degeneration and was considered a candidate for the muscle-derived neurotrophic activity that regulates motor neuron survival during development. However, CNTF expression is very low in the embryo, and CNTF gene mutations in mice or human do not result in notable abnormalities of the developing nervous system. We have generated and directly compared mice containing null mutations in the genes encoding CNTF or its receptor (CNTFR alpha). Unlike mice lacking CNTF, mice lacking CNTFR alpha die perinatally and display severe motor neuron deficits. Thus, CNTFR alpha is critical for the developing nervous system, most likely by serving as a receptor for a second, developmentally important, CNTF-like ligand.