IRSp53 is an adaptor protein that acts downstream of Rac and Cdc42 small GTPases and is implicated in

The clearance of Ca 2ϩ from nerve terminals is critical for determining the build-up of residual Ca 2ϩ after repetitive presynaptic activity. We found previously that K

We investigated Ca2+ clearance mechanisms (CCMs) at the axon terminals of mammalian central neurons: neurohypophysial (NHP) axon terminals and calyces of Held. Ca2+ transients were evoked by applying a short depolarization pulse via a patch pipette containing Ca2+ indicator dye. Quantitative analysis of the Ca2+ decay phases revealed that Na+/Ca2+ exchange (Na/CaX) is a major CCM at both axon terminals. In contrast, no Na/CaX activity was found in the somata of NHP axon terminals (supraoptic magnocellular neurons), indicating that the distribution of Na+/Ca2+ exchangers is polarized. Intracellular dialysis of axon terminals with a K+-free pipette solution attenuated the Na/CaX activities by 90% in the NHP axon terminals and by 60% at the calyx of Held, indicating that K+-dependent Na+/Ca2+ exchangers are involved. Studying the effects of specific inhibitors of smooth endoplasmic reticulum Ca2+-ATPase (SERCA) and plasma membrane Ca2+-ATPase (PMCA) on the Ca2+ decay rate revealed that PMCA contributed 23% of total Ca2+ clearance, but that SERCA made no contribution at the calyx of Held. The contribution of mitochondria was negligible for small Ca2+ transients, but became apparent at peak Ca2+ levels higher than 2.5 microM. When mitochondrial function was inhibited, the dependence of CCMs on [Ca2+]i at the calyx of Held showed saturation kinetics with K(1/2) = 1.7 microM, suggesting that the Na/CaX activity is saturated at high [Ca2+]i. The presynaptic Na+/Ca2+ exchanger activity, which competes for cytosolic Ca2+ with mitochondria, may contribute to nonplastic synaptic transmission at these axon terminals.

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Despair is a core symptom of depressive disorders. However, little is known about the neural circuits mediating despair and how they are modified by antidepressants. Here we show that the balance between excitatory and inhibitory neurotransmission (E/I balance) in the hippocampus affects behavioral despair in mice. Reduced interneuron density, knockdown of Gabrg2 or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons rapidly induced despair-like behaviors. Disinhibition induced by the GABAAR antagonist pentylenetetrazol produced transient antidepressant effects without BDNF elevation in the hippocampus, while ketamine exhibited rapid and sustained antidepressant effects, but the latter was sensitive to the TrkB receptor blocker ANA-12. These results suggest that rapid disinhibition and BDNFinduced long-lasting synaptic modification leads to enhanced E/I balance, which may contribute to acute and sustained behavioral effects of rapid-acting antidepressants.

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