Neurobiology of disease
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Neurobiology of disease · Jan 2019
The characteristics of pallidal low-frequency and beta bursts could help implementing adaptive brain stimulation in the parkinsonian and dystonic internal globus pallidus.
Adaptive deep brain stimulation (aDBS) has been applied in Parkinson's disease (PD), based on the presence of brief high-amplitude beta (13-35 Hz) oscillation bursts in the subthalamic nucleus (STN), which correlate with symptom severity. Analogously, average low-frequency (LF) oscillatory power (4-12 Hz) in the internal globus pallidus (GPi) correlates with dystonic symptoms and might be a suitable physiomarker for aDBS in dystonia. Characterization of pallidal bursts could facilitate the implementation of aDBS in the GPi of PD and dystonia patients. ⋯ Pallidal LF and beta burst amplitudes have different characteristics in PD and dystonia. The presence of increased burst amplitudes could be employed as feedback for GPi-aDBS.
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Neurobiology of disease · Jan 2019
Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway.
Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. ⋯ Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.
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Neurobiology of disease · Jan 2019
A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome.
Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p. ⋯ Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.
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Neurobiology of disease · Jan 2019
NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology.
In the striatum, specific N-methyl-d-aspartate receptor (NMDAR) subtypes are found in different neuronal cells. Spiny projection neurons (SPNs) are characterized by NMDARs expressing GluN2A and GluN2B subunits, while GluN2D is exclusively detected in striatal cholinergic interneurons (ChIs). In Parkinson's disease (PD), dopamine depletion and prolonged treatment with levodopa (L-DOPA) trigger adaptive changes in the glutamatergic transmission from the cortex to the striatum, also resulting in the aberrant function of striatal NMDARs. ⋯ Moreover, immunohistochemistry and electrophysiology experiments reveal that GluN2D-NMDARs are expressed not only by striatal ChIs but also by SPNs in dyskinetic rats. Notably, in vivo treatment with a well-characterized GluN2D antagonist ameliorates the severity of established dyskinesia in L-DOPA-treated animals. Our findings support a role for GluN2D-NMDARs in LID, and they confirm that cell-type and subunit specific modifications of NMDARs underlie the pathophysiology of LID.