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

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

Homeostatic plasticity in neuronal cultures from the YAC128 Huntington disease model mouse

Huntington disease (HD) is an inherited neurodegenerative disorder caused by expansion of the CAG repeat region of the huntingtin (Htt) gene. Early in the disease neuronal degeneration is preceded by synaptic dysfunction and changes in cellular signaling. This includes reduced BDNF signaling and altered calcium homeostasis, which could interfere with the group of processes known as homeostatic plasticity which alter neuronal connectivity and excitability to maintain neuronal network stability. We compared neurons cultured from normal (wild-type) mice with those from mice expressing the human genomic DNA for mutant huntingtin (YAC128). We focused on synaptic scaling, the process whereby the strength of synapses onto a neuron changes based on its level of activity. This is typically measured using the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs), which represent the response to neurotransmitter release from individual synaptic vesicles. We attempted to induce scaling at excitatory glutamatergic synapses in striatal projection neurons (SPNs) in cortico-striatal co-cultures, and in cortical pyramidal neurons (CPNs) in cortical mono-cultures, by suppressing activity with tetrodotoxin (TTX) or disinhibiting activity with bicuculline (BIC) over 48 hours. This failed to induce homeostatic plasticity in either wild-type or YAC128 SPNs; however, TTX did induce an increase in synaptic AMPA receptor content and glutamatergic synapse density in wild-type (WT) CPNs, which was reflected in increased mEPSC amplitude and frequency. In CPNs from YAC128 HD mice this occurred only after pre-treatment with pridopidine – a drug previously tested in HD clinical trials – or the sigma-1 receptor (S1R) agonist 3-PPP. These data, combined with the results of manipulating culture medium BDNF concentration in WT CPN cultures, led us to conclude that impairment and restoration of homeostatic plasticity in YAC128 CPNs depends on changes to multiple signaling pathways modulated by S1R, including BDNF signaling. These results suggest that cortical homeostatic plasticity at glutamatergic cortical synapses is disrupted early in HD and may play a role in the disease’s early cognitive and psychiatric symptoms. They also indicate that S1R agonists can ameliorate this disruption, adding to the evidence that drugs of this class may be of use in treating the early symptoms of HD.Medicine, Faculty ofGraduat

Endocannabinoid-specific impairment in synaptic plasticity in striatum of Huntington's disease mouse model

Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Prior to a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs. Indirect pathway SPNs, which are more vulnerable in Huntington's disease, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in Huntington's disease

Purkinje cell axonal swellings enhance action potential fidelity and cerebellar function

Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning.</p