Differential Activation of Calpain-1 and Calpain-2 following Kainate-Induced Seizure Activity in Rats and Mice.

Systemic injection of kainate produces repetitive seizure activity in both rats and mice. It also results in short-term synaptic modifications as well as delayed neurodegeneration. The signaling cascades involved in both short-term 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 being 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 (phosphatase and tensin homolog; 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-positive 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.

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.