Hippocampal synaptic metaplasticity requires inhibitory autophosphorylation of Ca2+/calmodulin-dependent kinase II.

Virtually all CNS synapses display the potential for activity-dependent long-term potentiation (LTP) and/or long-term depression (LTD). Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully modulated by previous synaptic activity. This higher-order form of plasticity has been termed metaplasticity. Here, we show that inhibitory autophosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) is required for hippocampal metaplasticity at the lateral perforant path-dentate granule cell synapse. Brief 10 Hz priming, which does not affect basal synaptic transmission, caused a dramatic, pathway-specific and long-lasting (up to 18 h) reduction in subsequently evoked LTP at lateral perforant path synapses. In contrast, LTD was unaffected by priming. The induction of lateral perforant path metaplasticity required the activation of NMDA receptors during priming. In addition, metaplasticity was absent in knock-in mice expressing alphaCaMKII that cannot undergo inhibitory phosphorylation, indicating that inhibitory autophosphorylation of alphaCaMKII at threonines 305/306 is required for metaplasticity. Metaplasticity was not observed in the medial perforant pathway, consistent with the observation that CaMKII activity was not required for the induction of LTP at this synapse. Thus, modulation of alphaCaMKII activity via autophosphorylation at Thr305/Thr306 is a key mechanism for metaplasticity that may be of importance in the integration of temporally separated episodes of activity.

Analysis of pThr286-CaMKII and CaMKII immunohistochemistry in the hippocampus of patients with temporal lobe epilepsy.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates a variety of neuronal proteins, thereby, coordinating responses to changes of intracellular Ca2+ concentrations. Autophosphorylation at threonine286 generates an autonomously active form of CaMKII (pThr286-CaMKII), thus prolonging responses to transient increases in Ca2+. Our previous studies in hippocampi of temporal lobe epilepsy (TLE) patients revealed a significant up-regulation of CaMKII in dentate granule cells (DGCs) of specimens with Ammon's horn sclerosis (AHS). However, the functional status of the up-regulated enzyme remained unclear. Therefore, we performed double immunofluorescence staining for CaMKII and pThr286-CaMKII in hippocampi of TLE patients and controls. Furthermore, we analyzed the ratio of the relative fluorescence intensities pThr286-CaMKII: CaMKII in DGCs. CaMKII immunoreactivity was significantly increased in DGC bodies and their proximal dendrites in AHS. In contrast, immunostaining for pThr286-CaMKII was localized to the DGC bodies, revealing similar labeling intensities in all TLE and control specimens, and was not observed in the dendritic compartment of DGCs. Analysis of the ratio of the relative fluorescence intensities pThr286-CaMKII:CaMKII in DGC bodies revealed a significantly reduced ratio in AHS compared to lesion-associated TLE and controls. Thus, up-regulation of total CaMKII in DGCs of AHS specimens is not paralleled by an increase of its autonomously active form.

N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice.

Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-amino-acid-oxidase (DAO) and as a mitochondrial protein. We recently generated 'humanized' bacterial artificial chromosome transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine. Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.