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