Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease

Abstract

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the huntingtin gene. The onset of symptoms is preceded by synaptic dysfunction. Homeostatic synaptic plasticity (HSP) refers to processes that maintain the stability of networks of neurons, thought to be required to enable new learning and cognitive flexibility. One type of HSP is synaptic scaling, in which the strength of all of the synapses onto a cell increases or decreases following changes in the cell’s level of activity. Several pathways implicated in synaptic scaling are dysregulated in HD, including brain-derived neurotrophic factor (BDNF) and calcium signaling. Here, we investigated whether HSP is disrupted in cortical neurons from an HD mouse model. We treated cultured cortical neurons from wild-type (WT) FVB/N or YAC128 HD mice with tetrodotoxin (TTX) for 48 h to silence action potentials and then recorded miniature excitatory postsynaptic currents. In WT cultures, these increased in both amplitude and frequency after TTX treatment, and further experiments showed that this was a result of insertion of AMPA receptors and formation of new synapses, respectively. Manipulation of BDNF concentration in the culture medium revealed that BDNF signaling contributed to these changes. In contrast to WT cortical neurons, YAC128 cultures showed no response to action potential silencing. Strikingly, we were able to restore the TTX-induced changes in YAC128 cultures by treating them with pridopidine, a drug which enhances BDNF signaling through stimulation of the sigma-1 receptor (S1R), and with the S1R agonist 3-PPP. These data provide evidence for disruption of HSP in cortical neurons from an HD mouse model that is restored by stimulation of S1R. Our results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD.

Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible

“…The reduction in spine density was found to be reversible in D2-MSN but not in in D1-MSN [21][22][23]. Dendritic pruning, in contrast, was not reversible [8]. This indicates that reversibility requirements may differ between D1 and D2 MSN and between spine density and TDL.…”

“…For instance, D2-MSN are disinhibited by dopamine depletion. The homeostatic response in the face of chronic dopamine depletion includes a decrease in electrical excitability and a reduced number of glutamatergic synapses [8]. A lower density of dendritic spines and a pruned dendritic tree was also observed in further animal models [9,[13][14][15][16][17][18] and in striatal MSN of PD patients [19,20].…”

“…Homeostatic plasticity allows neuronal networks to maintain a stable rate of activity when synapses change [5]. This has been studied mainly during development and learning [5,6], but also in the course of neurological and psychiatric diseases [7][8][9][10]. In humans and animal models, chronic dopaminergic depletion and substitution can induce plastic changes that differ from acute effects and that are potentially mediated by homeostatic plasticity mechanisms.…”

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

“…BDNF overexpression is sufficient to rescue many phenotypic characteristics of YAC128 HD mice (e.g., motor performance, cognitive deficits, synaptic density) (Xie et al, 2010), further suggesting that BDNF signaling could be an important contributor to neuroprotection following S1R activation. The idea that some of the beneficial effects of pridopidine in HD models can be mediated through BDNF signaling was supported by recent experimental evidence from Smith-Dijak et al (2019). Synaptic scaling was suppressed in YAC128 cultures, as determined by recording the amplitude and frequency of mEPSCs after blockade of activity-dependent neurotransmission with TTX.…”

Alterations in synaptic function and plasticity in Huntington disease

“…This idea is supported by the association between decreased cortical expression of Kalirin‐7, a guanine‐nucleotide exchange factor involved in maintenance of dendritic spines, and development of a cognitive phenotype in HD model mice (Puigdellívol et al, ). If indeed impaired HSP contributes to cognitive deficits in HD, then treatment with pridopidine may provide additional benefits in ameliorating such symptoms, since it restores HSP at glutamatergic cortical synapses in cultures from HD mice (Smith‐Dijak et al, ). Further investigation of impairment of HSP in HD may shed more light on the mechanisms underlying these symptoms, and the pathogenesis of HD more generally.…”