Review articleCalpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

•The ischemia-induced [Ca2+]i increase upregulates calpain activity in neurons.•Calpains target proteins in GABAergic and glutamatergic synapses.•In brain ischemia calpains cleave pre- and post-synaptic proteins.•Calpain-mediated protein cleavage contributes to neuronal death in brain ischemia.•Targeting calpain-dependent mechanisms may be a good therapeutic approach for stroke.

The excessive extracellular accumulation of glutamate in the ischemic brain leads to an overactivation of glutamate receptors with consequent excitotoxic neuronal death. Neuronal demise is largely due to a sustained activation of NMDA receptors for glutamate, with a consequent increase in the intracellular Ca2+ concentration and activation of calcium- dependent mechanisms. Calpains are a group of Ca2+-dependent proteases that truncate specific proteins, and some of the cleavage products remain in the cell, although with a distinct function. Numerous studies have shown pre- and post-synaptic effects of calpains on glutamatergic and GABAergic synapses, targeting membrane- associated proteins as well as intracellular proteins. The resulting changes in the presynaptic proteome alter neurotransmitter release, while the cleavage of postsynaptic proteins affects directly or indirectly the activity of neurotransmitter receptors and downstream mechanisms. These alterations also disturb the balance between excitatory and inhibitory neurotransmission in the brain, with an impact in neuronal demise. In this review we discuss the evidence pointing to a role for calpains in the dysregulation of excitatory and inhibitory synapses in brain ischemia, at the pre- and post-synaptic levels, as well as the functional consequences. Although targeting calpain-dependent mechanisms may constitute a good therapeutic approach for stroke, specific strategies should be developed to avoid non-specific effects given the important regulatory role played by these proteases under normal physiological conditions.