Abstract
Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry.
Highlights
Interneurons play a crucial role in balancing neuronal activity in the brain[1]
To determine if specific interneuron populations were altered in the SOD1 cortex, we used immunohistochemistry to assess the potential changes in the numbers of interneuron populations in the motor and somatosensory cortex of late-symptomatic (20 week) SOD1 mice, and in age and litter-matched wild type (WT) controls
GABAergic interneuron subtypes were differentiated according to the selective expression of calcium binding proteins [calbindin (CB), calretinin (CR), parvalbumin (PV)] and neuropeptides [neuropeptide Y (NPY), somatostatin (SOM), vasoactive intestinal peptide (VIP)]19 (Fig. 2a–f)
Summary
In the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS), the loss of inhibitory interneuronal activity has been associated with the development of cortical hyperexcitability, linked to the onset of motor neuron degeneration that characterises the disease (for reviewed in[2,3,4]) Present in both sporadic and familial forms of ALS5–10, inhibitory dysfunction manifests in the motor cortex as reduced short-interval intracortical inhibition (SICI), which in combination with increased glutamate activity, is thought to cause cortical hyperexcitability[11,12]. This pathophysiological phenomenon is identified in the motor cortex of patients prior to lower motor neuron dysfunction[13]; suggesting early changes in the balance between excitation and inhibition in the cortex may initiate, or in the very least, exacerbate, ALS pathology. This data suggests NPY- and CR-interneurons are involved in a motor-specific inhibitory phenotype from early stages in disease – thereby demonstrating the potential for an underlying inhibitory contribution in the SOD1 mouse model of ALS
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