Abstract
Amyotrophic lateral sclerosis (ALS) is characterised by the death of upper (corticospinal) and lower motor neurons (MNs) with progressive muscle weakness. This incurable disease is clinically heterogeneous and its aetiology remains unknown. Increased excitability of corticospinal MNs has been observed prior to symptoms in human and rodent studies. Increased excitability has been correlated with structural changes in neuronal dendritic arbors and spines for decades. Here, using a modified Golgi-Cox staining method, we have made the first longitudinal study examining the dendrites of pyramidal neurons from the motor cortex, medial pre-frontal cortex, somatosensory cortex and entorhinal cortex of hSOD1G93A (SOD1) mice compared to wild-type (WT) littermate controls at postnatal (P) days 8–15, 28–35, 65–75 and 120. Progressive decreases in dendritic length and spine density commencing at pre-symptomatic ages (P8-15 or P28-35) were observed in layer V pyramidal neurons within the motor cortex and medial pre-frontal cortex of SOD1 mice compared to WT mice. Spine loss without concurrent dendritic pathology was present in the pyramidal neurons of the somatosensory cortex from disease-onset (P65-75). Our results from the SOD1 model suggest that dendritic and dendritic spine changes foreshadow and underpin the neuromotor phenotypes present in ALS and may contribute to the varied cognitive, executive function and extra-motor symptoms commonly seen in ALS patients. Determining if these phenomena are compensatory or maladaptive may help explain differential susceptibility of neurons to degeneration in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease [11] and is clinically characterised by the death of upper and lower motor neurons (MNs) and the degeneration of the corticospinal tract [10, 25]
Cortical thickness is reduced in somatosensory cortex and entorhinal cortex of hSOD1G93A (SOD1) mice by P28-35 in the motor cortex, and by P120. By mid-disease (P120) in the medial pre-frontal cortex (MPFC) and in the somatosensory cortex, compared to WT controls Imaging studies have shown thinning of various cortical regions, including those containing upper MNs, as well as their axonal tract projections in ALS patients [55, 71, 74]
A variety of pathogenic process may be contributing to cortical thinning in ALS, we assessed whether this occurred in the SOD1 mice at different ages and brain regions, namely the motor cortex, the MPFC, entorhinal cortex and the somatosensory cortex
Summary
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease [11] and is clinically characterised by the death of upper and lower motor neurons (MNs) and the degeneration of the corticospinal tract [10, 25]. Structural abnormalities in the dendritic arbors and/or dendritic spines of neurons from the most widely used ALS rodent model, the hSOD1G93A transgenic mouse (SOD1), have been reported in upper MNs from the motor cortex [20, 30, 53, 58] and medial pre-frontal cortex (MPFC) [57], as well as lower MNs in the brainstem [69] and spinal cord [40] These studies provide some insight into individual components of the neuromotor network, there remains a need to characterize structural abnormalities in motor, cognitive, sensory and extra-motor regions at differing stages of disease, to reveal whether changes in neuron structure occur prior to, and are confined to, vulnerable neurons, compared to non-vulnerable neurons. We have characterized changes in neuronal structure in motor-related populations (motor cortex and somatosensory cortex) severely affected in ALS [10, 11, 15, 24, 25, 27, 32, 63, 65], and in cortical regions associated with cognitive function deficits (the MPFC and entorhinal cortex) in a subset of ALS patients [37, 38, 47, 63]
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