Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

Differential sensitivity of skeletal and fusimotor neurons to Bcl-2-mediated apoptosis during neuromuscular development.

Proper development of the nervous system requires that a carefully controlled balance be maintained between both proliferation and neuronal survival. The process of programmed cell death is believed to play a key role in regulating levels of neuronal survival, in large part through the action of antiapoptotic proteins, such as Bcl-2. Consistent with this, Bcl-2 has been shown to be a key regulator of apoptotic signaling in post-mitotic neurons. However, we still know remarkably little regarding the role that Bcl-2 plays in regulating the survival of specific motor neuron populations. In the present study, we have examined somatic motor neurons of the lumbar spinal cord, and branchiomotor neurons of the facial nucleus in bcl-2-null mice to determine the differential dependence among motor neuron populations with respect to Bcl-2-mediated survival. Examination of neuronal and axon number, axonal area, and the distribution of axonal loss in bcl-2-null mice demonstrates that, in contrast to the great majority of alpha motor neurons, gamma motor neurons exhibit a unique dependence upon bcl-2 for survival. These results demonstrate, for the first time, the connection between Bcl-2 expression, motor neuron survival, and the establishment of different motor populations.

The number and sizes of reconstructed peripheral autonomic, sensory and motor neurons in a case or dysautonomia.

Motor, spinal ganglion, intermediolateral and sympathetic trunk neurons were reconstructed by morphometric sampling of their cell bodies at L5 and T7 segments and at various levels of spinal roots and peripheral nerves in a 31-year-old patient with dysautonomia and compared to reference cases. The patient had strikingly fewer intermediate motoneuron column neurons and intermediate ventral root axons (probably gamma motoneurons), spinal ganglion neurons, preganglionic autonomic neurons and sympathetic trunk neurons that did controls (approximately 10--30% of reference values). The striking agreement between selective absence of intermediate-diameter cytons (Ci) and of intermediate diameter myelinated fibers (Ai), which are thought to be gamma efferent, of L5 motoneuron columns provides further confirmation to our previous suggestion that the Ci peak of motoneuron columns are somas of gamma efferent neurons. The number and size of alpha motoneuron cell bodies and their proximal axons were like those of controls but their distal axons were probably atrophic. This finding probably explains the small reduction in maximum conduction velocity of motor nerve fibers found in this disorder. The brunt of the pathologic process in this disorder has been borne by intermediate and small neurons preferentially.

Pathology of myelinated fibers in cervical and lumbar ventral spinal roots in amyotrophic lateral sclerosis.

Pathological alterations were evaluated by morphometry and by a teased-fiber study on the 6th cervical (C6) and the 4th lumbar (L4) ventral spinal roots of cases of amyotrophic lateral sclerosis (ALS). The large-diameter fibers were severely affected in both spinal segments. However, small-diameter myelinated fibers were numerically well preserved. The number of large fibers in C6 and L4 ventral roots was strongly correlated to the strength of muscles innervated by C6 or L4 segments. There was no correlation of the number of small fibers with muscle strength. Teased fiber studies revealed a marked increase in the incidence of fibers showing axonal degeneration. Fibers considered to be regenerative were rarely observed. These observations suggest that large myelinated fibers, which correspond to alpha-motoneuron fibers, are selectively affected, and that small myelinated fibers, which are considered to correspond to gamma-motoneuron fibers, are preserved to some extent in the C6 and L4 ventral spinal roots in ALS.