Abstract
Objective: Motor neurons (MNs) die in amyotrophic lateral sclerosis (ALS), a clinically heterogeneous neurodegenerative disease of unknown etiology. In human or rodent studies, MN loss is preceded by increased excitability. As increased neuronal excitability correlates with structural changes in dendritic arbors and spines, we have examined longitudinal changes in dendritic structure in vulnerable neuron populations in a mouse model of familial ALS.Methods: We used a modified Golgi-Cox staining method to determine the progressive changes in dendritic structure of hippocampal CA1 pyramidal neurons, striatal medium spiny neurons, and resistant (trochlear, IV) or susceptible (hypoglossal, XII; lumbar) MNs from brainstem and spinal cord of mice over-expressing the human SOD1G93A (SOD1) mutation, in comparison to wild-type (WT) mice, at four postnatal (P) ages of 8–15, 28–35, 65–75, and 120 days.Results: In SOD1 mice, dendritic changes occur at pre-symptomatic ages in both XII and spinal cord lumbar MNs. Spine loss without dendritic changes was present in striatal neurons from disease onset. Spine density increases were present at all ages studied in SOD1 XII MNs. Spine density increased in neonatal lumbar MNs, before decreasing to control levels by P28-35 and was decreased by P120. SOD1 XII MNs and lumbar MNs, but not trochlear MNs showed vacuolization from the same time-points. Trochlear MN dendrites were unchanged.Interpretation: Dendritic structure and spine alterations correlate with the neuro-motor phenotype in ALS and with cognitive and extra-motor symptoms seen in patients. Prominent early changes in dendritic arbors and spines occur in susceptible cranial and spinal cord MNs, but are absent in MNs resistant to loss in ALS.
Highlights
In amyotrophic lateral sclerosis (ALS) both upper and lower motor neurons (MNs), as well as the corticospinal tract, undergo progressive degeneration (Charcot and Joffroy, 1869; Cleveland and Rothstein, 2001)
There are no longitudinal studies of dendritic morphology and spine density of several subcortical and motor neuron populations in any rodent model of ALS
We present a number of new insights, showing that morphological changes occur in medium spiny neurons (MSNs) from the dorsal striatum, brainstem XII MNs, and lumbar MNs, but not in hippocampal CA1 pyramidal neurons, and brainstem IV MNs
Summary
In amyotrophic lateral sclerosis (ALS) both upper and lower motor neurons (MNs), as well as the corticospinal tract, undergo progressive degeneration (Charcot and Joffroy, 1869; Cleveland and Rothstein, 2001). The Golgi-Cox technique has demonstrated significant structural changes, including dendritic shortening and decreased spine density, in upper and lower motor neurons of ALS patients and animal models of familial ALS (Hammer et al, 1979; Horoupian et al, 1984; Udaka et al, 1986; Kato et al, 1987; Fogarty et al, 2016c) These structural abnormalities are correlated with cortical hyper-excitability (Eisen et al, 1993; Mills and Nithi, 1997; Zanette et al, 2002; Turner et al, 2005; Vucic and Kiernan, 2006; Fogarty et al, 2015, 2016b), which can be observed before diagnosis in certain ALS patients (Vucic et al, 2008), suggesting that protracted preclinical structure/function alterations play a key role in disease pathogenesis (van Zundert et al, 2012; Eisen et al, 2014). Glutamatergic neurotransmission is thought to be a significant regulator of dendritic structure, and glutamatergic excitotoxicity is one proposed mechanism in ALS pathogenesis (Eisen et al, 1993; Mills and Nithi, 1997; van Zundert et al, 2008, 2012; Bogaert et al, 2010; Bellingham, 2011; Turner et al, 2013; Devlin et al, 2015; Fogarty et al, 2015, 2016b; Saba et al, 2015)
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