I definitely had a delightful session this afternoon. Lots of noteworthy posters. I stopped at a couple, however, I will discuss my absolute favorite poster of the day.
Poster #1: Kv1.3 mediates cholinergic hyperexcitability in a mouse model of Parkinson’s disease
*C. TUBERT1, I. R. E. TARAVINI2, G. SANCHEZ3, A. PROST1, L. RELA1, M. G. MURER1;
1Ifibio-Houssay-Conicet-University of Buenos Aires, Capital Federal, Argentina; 2Ininfa-Conicet-University of Buenos Aires, Capital Federal, Argentina; 3Departament of Physiology-School of Medicin-University of Buenos Aires, Capital Federal, Argentina
Cholinergic neurons which are known to exhibit a pause in response to dopamine neuron bursts in a reward context, lose their ability to pause in Parkinson’s disease. This pause is reflected as a slow AHP (after-hyperpolarization) that is not well understood in these neurons. During sustained firing in response to current injections, cholinergic neurons typically fire in response to depolarizing inputs, and are able to sustain their firing, without showing any accommodation… however, this is only in Juvenile mice. In adults, this is lost (they show accommodation). Interestingly, however, adult Parkinsonian mice (6 hydroxydopamine lesioned) show this same absence of accommodation as in normal juvenile mice. So the question then emerges, what ionic current mediates this difference in accommodation and how is that related to the pause that is often seen in cholinergic neurons in response to dopamine neuron bursts?
They used invitro electrophysiology in juvenile control and 6-OHDA lesioned mice to investigate the difference in the accommodation phenomenon.
First, they observed a larger ratio of non-accommodating cholinergic neurons in the juvenile mice, showing a developmental down regulation, compared to adult mice. They then pharmacologically attempted to isolate the ionic current that contributed to the accommodation. They tested frequency-intensity curves in the presence of Margotoxin ( MgTx – a Kv1.3 channel blocker) and alpha-Dendrotoxin (DTX – a Kv1.1, Kv1.2 and Kv1.6 channel blocker) and both significantly led to an increase in the firing rates of the neurons, and elimination of accommodation. They had suspected that Kv7 contributed to the accommodation, however that was not the case.
Next, they examined the currents underlying the differences in excitability by examining the ramp currents, and observed a nice reduction in the overall currents in response to to MgTX which correlated nicely with the timing of the last spike within the same neuron (the timing is a measure of the accommodation). Due to the promiscuous nature of DTX blocking two Kv currents, they carried out laser capture micro dissection (LCM) that allowed them to isolate specific cells and subsequently run a RT-PCR to examine the presence of the Kv channels… turns out only Kv1.1 and Kv1.3 are present in the cholinergic neurons.
So at this point, not only have they established that there is an accommodating phenotype that is present in adult cholinergic neurons, absent in Juvenile and Parkinsonian cholinergic neurons, but they show that Kv1.1 and Kv1.3 currents mediate that accommodation. The question that remains is this – is there a change in the Kv1.1 and Kv1.3 currents in the Parkinsonian Cholinergic neurons? They examined 6-OHDA mice and as opposed the control, there is a larger degree of non-accommodating cholinergic neurons, similar to what was observed among the Juvenile control cholinergic neurons. And – yes, you guessed it! There was a down-regulation of the Kv1.3 currents (MgTX3 sstv currents) in the 6-OHDA cholinergic neurons present in these neurons (6-OHDA – Cholinergic).
Lastly, they examined the “pause” that results in the cholingeric neurons in response to the dopamine neuron burst, by examining the slow AHP. What they find is that the MgTX sstv current, Kv1.3 current, does mediate the slow AHP.
In essence, what they observe is a neat mechanistic adjustment that occurs in the cholinergic neurons as a result of dopaminergic loss during Parkinson’s – the down regulation of Kv1.3 currents that would strongly silence the cholinergic neurons in response to dopamine neurons bursts had it still been present.
I thoroughly enjoyed this poster, mostly because it is right up my alley of ion channels being involved in disease mechanism. I would be interested in knowing at what stage this change occurs as the disease progresses, is this a homeostatic change due to the loss of the dopamine neurons, and what functional circuit reorganization occurs as a result of the change where the ability for the cholinergic neurons to pause is lost.
I also had other posters I really enjoyed, however, I am going to give a shout-out instead of a summary:
- The background sodium channel NALCN regulates basal excitability of chemosensitive retrotrapezoid nucleus neurons and stimulation of breathing by CO
*Y. SHI, C. ABE, B. HOLLOWAY, S. SHU, E. PEREZ-REYES, R. STORNETTA, P. GUYENET, D. BAYLISS;
Univ. of Virginia, Charlottesville, VA
*M. N. NENOV1, F. SCALA2,1, E. CROFTON1, Y. ZHANG1, N. PANOVA1, T. GREEN1, M. D’ASCENZO2, F. LAEZZA1;
1Pharmacol. and Toxicology, Univ. of Texas Med. Br., Galveston, TX; 2Inst. of Human Physiology, Med. School, Univ. Cattolica, Rome, Italy
*C. L. COMBE1, R. TIKIDJI-HAMBURYAN2, C. C. CANAVIER3, S. GASPARINI4;
1Neurosci. Ctr., 2Dept. of Cell Biol. and Anat., 3Dept. of Cell Biol. and Anatomy, Neurosci. Ctr., 4Neurosci. Center, Dept. of Cell Biol. and Anat., Louisiana State Univ. Hlth. Sci. Ctr., New Orleans, LA