presentation - robinson j - the role of pannexin1 channels in seizure activity (1)

The Role of Pannexin1 Channels in Seizure Activity

in vivo and in vitro

Jordan Robinson

MSc Candidate

Teskey Lab / Thompson Lab

Pannexin1 Channel Expression

Adapted from:Zoidl et al 2007Santiago et al 2011

Panx1 contributes to aberrant burst firing

• Panx1 contributes to a secondary inward current

• Panx1 augments aberrant firing in an NMDA-dependent in vitro model of interictal burst firing

Thompson et al, 2008

Pannexin1 and Seizure Severity

• Panx1 block has paradoxical effects on seizure severity in the pilocarpine (left) and kainate (right) models of seizure and status epilepticus

Kim and Kang 2011 Santiago et al 2011

Research Questions

1. Does Panx1 contribute to the process of epileptogenesis?

2. Is Panx1 block pro- or anticonvulsant following kindling epileptogenesis?

3. Is Panx1 block pro- or anticonvulsant in the Pilocarpinemodel in rats?

4. Is the contribution of Panx1 to the local field excitability of the seizure focus altered following epileptogenesis?

The Electrical Kindling Model

A) Track of a stimulating/ recording electrode

B) Trace of a kindling stimulation-induced ‘afterdischarge’ (AD)

C) Repeated stimulation increases AD duration (ADD) as well as spike amplitude

Modified from: Paxinos and Watson 1982Goddard et al 1969

Panx1 Block Slows Kindling Epileptogenesis

• A single infusion of Panx1 blocker decrease A) the number of kindling sessions required for rats to become fully kindled and B) the rate at which rats become fully kindled.

Panx1 Block Decreases Seizure Severity in Fully Kindled Rats

Acute Hippocampal Slices

A. Stimulus waveform

B. Delivered to the Schaffer collaterals

C. Evokes a field potential

D. Composed of both the EPSP and the population spike.

Kindling does not alter field excitability or STP

A) Representative traces of evoked potentials elicited with a 300 uA stimulus

B) Kindling does not change the slope of the fEPSP compared to controls

C) Kindling does not alter short-term plasticity compared to controls

Panx1 block does not alter field excitability or STP

Panx1 Block Augments STP of the Population Spike

A) Sample traces of PS evoked under Panx1 block

B) The amplitude of the population spike is not altered by Panx1 block in kindled or control rats

C) The Paired-Pulse Ratio is increased following Panx1 block in both kindled and control rats

Panx1 is Anticonvulsant in the Pilocarpine Model in Rats

Panx1 block A) increases the latency to behavioural seizure and B) decreases seizure severity. However, Panx1 block does not alter seizure duration.

Summary

• I have presented the novel findings that:

1) A single Panx1 block is sufficient to persistently retard the course of epileptogenesis (!)

2) Panx1 block decreases seizure severity in fully kindled rats

3) Panx1 block is robustly anticonvulsant in the Pilocarpinemodel

4) Panx1 block augments STP at the CA3-CA1 synapse in vitro

Acknowledgements

• Dr. Teskey and Dr. Thompson as well as all the members of the Teskey and Thompson Labs

• Funding Sources: