Essential function of α-calcium/calmodulin-dependent protein kinase II in neurotransmitter release at a glutamatergic central synapse

Abstract

A significant fraction of the total calcium͞calmodulin-dependent protein kinase II (CaMKII) activity in neurons is associated with synaptic connections and is present in nerve terminals, thus suggesting a role for CaMKII in neurotransmitter release. To determine whether CaMKII regulates neurotransmitter release, we generated and analyzed knockout mice in which the dominant ␣-isoform of CaMKII was specifically deleted from the presynaptic side of the CA3-CA1 hippocampal synapse. Conditional CA3 ␣-CaMKII knockout mice exhibited an unchanged basal probability of neurotransmitter release at CA3-CA1 synapses but showed a significant enhancement in the activity-dependent increase in probability of release during repetitive presynaptic stimulation, as was shown with the analysis of unitary synaptic currents. These data indicate that ␣-CaMKII serves as a negative activity-dependent regulator of neurotransmitter release at hippocampal synapses and maintains synapses in an optimal range of release probabilities necessary for normal synaptic operation. Synapses mediate interneuronal communication and display a variety of properties (1). Presynaptic neurotransmitter release is one of the first steps in the sequence of events underlying synaptic transmission. Discrete packets of neurotransmitter encased in vesicles are released at synaptic connections with a certain probability (probability of release, P r ) in a tightly regulated fashion (1, 2). Calcium͞calmodulin-dependent protein kinase II (CaMKII), a serine͞threonine protein kinase, is well positioned to serve a role in synaptic function regulation, because it is highly expressed in the brain and is known to phosphorylate multiple synaptic proteins (2). Accordingly, CaMKII has previously been implicated in the long-lasting frequency-dependent regulation of synaptic function in mammals (3-9), birds (10), frogs (11), and invertebrates (12).Although a postsynaptic role for CaMKII in synaptic function and plasticity has been well demonstrated (3,4,6,7,13), studies of the presynaptic function of this enzyme are scarce. Early microinjection experiments in the squid giant synapse showed that CaMKII injected presynaptically enhanced neurotransmitter release (14,15). This effect appeared to be mediated by phosphorylation of a synaptic vesicle protein, synapsin I, which in its dephosphorylated form inhibited synaptic transmission. However, mice lacking synapsin I do not demonstrate a major change in the basal P r (16), suggesting that certain differences in the mechanisms of release may exist between vertebrate and invertebrate synapses. It has also been shown that ␣-CaMKII can either potentiate or depress CA3-CA1 synapses in the hippocampus depending on the pattern of presynaptic activation. Pairedpulse facilitation (PPF), an index of presynaptic function, was decreased in the CA1 region of mice heterozygous for a global null mutation of ␣-CaMKII, whereas another form of presynaptic plasticity, which also depends on P r , posttetanic potentiation, was enhanced (17). A direct esti...

Chronic Antidepressants Induce Redistribution and Differential Activation of αCaM Kinase II between Presynaptic Compartments

“…Therefore, the antidepressant-induced change in aCaM kinase II phosphorylation seems to be a crucial event in the molecular modifications leading to modulation of glutamate release. Indeed, aCaM kinase II has been proposed to regulate probability of release in central synapses during high-frequency presynaptic stimulation (Hinds et al, 2003); the drug-induced molecular and functional changes we found related to aCaM kinase II are in line with this role for the enzyme. The mechanism whereby antidepressants may induce the adaptive changes we observed in aCaM kinase II is at present unknown.…”

Calmodulin Controls Synaptic Strength via Presynaptic Activation of Calmodulin Kinase II

“…5, available at www.jneurosci.org as supplemental material). The second mechanism appears most likely given previous studies (Llinás et al, 1985;Sakaba and Neher, 2001;Thiagarajan et al, 2002;Hinds et al, 2003;Dick et al, 2008), but the third mechanism cannot be excluded with the data up to now. Thus, to test the third mechanism, we performed two complementary sets of experiments (Fig.…”

“…The majority of neurotransmitter release is triggered by Ca 2ϩ binding to synaptotagmin (Fernández-Chacó n et al, 2001;Maximov and Südhof, 2005), but CaM may function as an ancillary Ca 2ϩ sensor for the asynchronous component of release, which is not mediated by synaptotagmin (Sun et al, 2007). Moreover, CaM may regulate the refilling of the readily-releasable pool (RRP) of vesicles (Sakaba and Neher, 2001) and/or modulate presynaptic release by activating calmodulin-dependent kinase-II␣ (CaMKII␣) and CaMKII␤ (Llinás et al, 1985;Thiagarajan et al, 2002;Hinds et al, 2003;Dick et al, 2008). Finally, CaM controls presynaptic and postsynaptic Ca 2ϩ -channel function (Lee et al, 2000;Dick et al, 2008), mediates postsynaptic long-term plasticity by activating CaMKII␣ and calcineurin (Lisman et al, 2002;Xia and Storm, 2005), and alters neuronal gene expression (Greer and Greenberg, 2008).…”

The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function

“…A possible explanation for the enhancement in learning seen on day 2 under the CAMKII inhibitor may be educed from experiments showing that CAMKII serves as an inhibitory constraint on hippocampal neurotransmitter release during high frequency presynaptic activity (Hinds et al, 2003). As KN-62 did not have any effect in sedentary controls, the effect of exercise on the synapse may be specifically related to the CAMKII system.…”