Lecture 11: Milnerwood and Raymond, 2007 Flashcards
What is huntington’s caused by?
It is an autosomal dominant mutation in the HTT (huntintin gene). Caused by greater than 35 repeats of CAG (polyglutamine).
What does huntington’s cause?
Massive loss of MSNs in caudate putamen (D2-receptor). Symptoms include cognitive deterioration, chorea, dystonia
What is the function of Huntintin protein?
It is involved with intracellular trafficking of organelles and proteins. It also increases transcription of BDNF, which supports neuron survival.
What do mutations in HTT do?
In WT, REST, a repressor, is bound by HTT, preventing it from associating with BDNF gene and repressing its transcription. In mutant, you get repression of BDNF. Also get disruption of intracellular transport.
What is the nigrostriatal pathway?
It is involved in movement, dopaminergic and glutamatergic neurons from the substantia nigra pars compacta will project to the caudate putamen (dorsal striatum).
Draw the circuitry of the direct and indirect paths of the basal ganglia
What is the excitotoxicity hypothesis?
That excessive release of NMDA kills neurons via exitotoxicity, which may be a mechanisms of neurodegeneration in huntington’s disease
What were the main findings about AMPA sEPSCs?
They had slightly more rapid inactivation, slightly lower frequency, longer inter-interval event, and slightly lower time constant. The amplitude of APMA currents was also smaller.
What were the differences in NT release probability?
They used paired pulses –> lower second pulse means higher initial probability of release. Found that more severe HTT resulted in significantly more facilitation –> less probability of AMPA current release.
What occurs to AMPA currents during repetitive stimulation?
In HTT mice, there is a reduction in EPSCs over repeated stimulation. Used axis resistance as a control to ensure that the decrease in current was not due to increasing axis resistance.
What were the main findings in AMPA eEPSCs?
There was a significantly reduced amplitude of eEPSCs in HT mice, there was no significant difference in time constant
What were the main findings about NDMA eEPSCs?
There was no difference in amplitude of eEPSCs, but there was significantly increased time constant in HT mice –> greater overall ion flux through NMDA receptors in the MSNs of HT mice
