Systemic injection of kainate produces repetitive seizure activity in both rats and mice. It also results in acute synaptic modifications as well as delayed neurodegeneration. The signaling cascades involved in both acute and delayed responses are not clearly defined. The calcium-dependent protease calpain is activated in various brain structures following systemic kainate injection, although the precise involvement of the two major brain calpain isoforms, calpain-1 and calpain-2, remains to be defined. It has recently been reported that calpain-1 and calpain-2 play opposite roles in NMDA receptor-mediated neuroprotection or neurodegeneration, with calpain-1 being neuroprotective and calpain-2 neurodegenerative. In the present study, we determined the activation pattern of calpain-1 and calpain-2 by analyzing changes in levels of different calpain substrates, including spectrin, drebrin, and PTEN (a specific calpain-2 substrate) in both rats and wild-type and calpain-1 knock-out mice. The results indicate that, while calpain-2 is rapidly activated in pyramidal cells throughout CA1 and CA3, rapid calpain-1 activation is restricted to parvalbumin- and to a lesser extent CCK-positive but not somatostatin-positive interneurons. In addition, calpain-1 knock-out mice exhibit increased long-term neurodegeneration in CA1, reinforcing the notion that calpain-1 activation is neuroprotective.
Significance Statement: Seizure activity results in both short- and long-term alterations in the structure and organization of neurons in hippocampus. While the activation of calpain has been well documented following kainic acid-induced seizures, there is no information regarding the roles of the two major calpain isoforms in the brain, calpain-1 and calpain-2, in the consequences of seizures. Here we report the surprising findings that while calpain-2 is rapidly activated in all pyramidal cells of CA1 and CA3, calpain-1 activation is restricted to a small population of interneurons following systemic KA injection. Furthermore, KA-induced neurodegeneration in CA1 is exacerbated in calpain-1 knock-out mice, further supporting the notion that calpain-1 is neuroprotective and calpain-2 neurodegenerative.
The authors declare no competing financial interest.
This work was supported by grant P01NS045260-01 from NINDS (PI: Dr. C.M. Gall). The authors want to thank Western University of Health Sciences for the financial support to MB. XB is also supported by funds from the Daljit and Elaine Sarkaria Chair.