No abstract

Although the maintenance mechanism of late long-term potentiation (LTP) is critical for the storage of long-term memory, the expression mechanism of synaptic enhancement during late-LTP is unknown. The autonomously active protein kinase C isoform, protein kinase M (PKM), is a core molecule maintaining late-LTP. Here we show that PKM maintains late-LTP through persistent N-ethylmaleimide-sensitive factor (NSF)/glutamate receptor subunit 2 (GluR2)-dependent trafficking of AMPA receptors (AMPARs) to the synapse. Intracellular perfusion of PKM into CA1 pyramidal cells causes potentiation of postsynaptic AMPAR responses; this synaptic enhancement is mediated through NSF/GluR2 interactions but not vesicle-associated membrane protein-dependent exocytosis. PKM may act through NSF to release GluR2-containing receptors from a reserve pool held at extrasynaptic sites by protein interacting with C-kinase 1 (PICK1), because disrupting GluR2/PICK1 interactions mimic and occlude PKM-mediated AMPAR potentiation. During LTP maintenance, PKM directs AMPAR trafficking, as measured by NSF/GluR2-dependent increases of GluR2/3-containing receptors in synaptosomal fractions from tetanized slices. Blocking this trafficking mechanism reverses established late-LTP and persistent potentiation at synapses that have undergone synaptic tagging and capture. Thus, PKM maintains late-LTP by persistently modifying NSF/GluR2-dependent AMPAR trafficking to favor receptor insertion into postsynaptic sites.

Protein synthesis-dependent forms of hippocampal long-term potentiation (late LTP) and long-term depression (late LTD) are prominent cellular mechanisms underlying memory formation. Recent data support the hypothesis that neurons store relevant information in dendritic functional compartments during late LTP and late LTD rather than in single synapses. It has been suggested that processes of "synaptic tagging" are restricted to such functional compartments. Here, we show that in addition to apical CA1 dendrites, synaptic tagging also takes place within basal CA1 dendritic compartments after LTP induction. We present data that tagging in the basal dendrites is restricted to these compartments. Plasticity-related proteins, partially nonspecific to the locally induced process, are synthesized in dendritic compartments and then captured by local, process-specific synaptic tags. We support these findings in two ways: (1) late LTP/LTD, locally induced in apical or basal (late LTP) dendrites of hippocampal CA1 neurons, does not spread to the basal or apical compartment, respectively; (2) the specificity of the synaptic plasticity event is achieved by the activation of process-and compartmentspecific synaptic tag molecules. We have identified calcium/calmodulin-dependent protein kinase II as the first LTP-specific and extracellular signal-regulated kinase 1/2 as LTD-specific tag molecules in apical dendritic CA1 compartments, whereas either protein kinase A or protein kinase M mediates LTP-specific tags in basal dendrites.

Protein kinase M (PKM) is a persistently active protein kinase C isoform that is synthesized during long-term potentiation (LTP) and is critical for maintaining LTP. According to "synaptic tagging," newly synthesized, functionally important plasticity-related proteins (PRPs) may prolong potentiation not only at strongly tetanized pathways, but also at independent, weakly tetanized pathways if synaptic tags are set. We therefore investigated whether PKM is involved in tagging and contributes to a sustained potentiation by providing strong and weak tetanization to two independent pathways and then disrupting the function of the kinase by a selective myristoylated -pseudosubstrate inhibitory peptide. We found that persistent PKM activity maintains potentiated responses, not only of the strongly tetanized pathway, but also of the weakly tetanized pathway. In contrast, an independent, nontetanized pathway was unaffected by the inhibitor, indicating that the function of PKM was specific to the tagged synapses. To further delineate the specificity of the function of PKM in synaptic tagging, we examined synaptic "cross-tagging," in which late LTP in one input can transform early into late long-term depression (LTD) in a separate input or, alternatively, late LTD in one input can transform early into late LTP in a second input, provided that the tags of the weak inputs are set. Although the PKM inhibitor reversed late LTP, it did not prevent the persistent depression at the weakly stimulated, cross-tagged LTD input. Conversely, although the agent did not reverse late LTD, it blocked the persistent potentiation of weakly tetanized, cross-tagged synapses. Thus, PKM is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and cross-tagging.

Canonical models suggest that mechanisms of long-term memory consist of a synapse-specific, protein synthesis-independent induction phase (changes in synaptic weights/temporary tagging of such synapses) and, within adjacent dendritic compartments, a protein synthesis-dependent distribution phase that may accompany or immediately precede induction and whose protein products enable consolidation through synaptic capture. We now report that this distribution phase is competitive in a "winner-take-all" fashion when synapses potentiated at induction compete with each other for plasticity-related proteins. This finding highlights the importance of synaptic competition in creating stable long-lasting memory in neural networks without disruption.A ctivity-dependent increases and decreases in synaptic efficacy, such as the physiological phenomena of long-term potentiation (LTP) and long-term depression, are considered to be prominent cellular mechanisms mediating learning and memory. Long-lasting persistence of synaptic strength requires protein synthesis that is achieved through transcription and translation (late LTP; L-LTP), whereas short-lasting changes do not involve protein synthesis (early LTP; E-LTP) (1). Based on this dependency on protein synthesis, a sequential model of memory has long been proposed involving the transition from E-LTP to L-LTP, and it remains an important framework for memory consolidation (2, 3). However, the newer concept of synaptic tagging and capture (STC) has changed our understanding of the necessity for a sequential framework. Instead, although memory encoding and tagging occur in real time in association with the event or stimulus to be remembered, the persistence of this trace depends also upon the capture of plasticity-related proteins (PRPs) whose synthesis can be triggered before, during, or immediately after memory encoding. The synthesis of PRPs, now thought to occur in relatively clustered dendritic domains (4, 5), creates the possibility for both synergistic (6) and competitive interactions between potential memories during the subsequent distribution phase. Synergistic effects are well-studied. However, although synaptic competition has been considered previously (7), the temporal dynamics of such competition are not well-understood. We now show that when the temporal persistence of synaptic potentiation is enabled on one pathway by virtue of the availability of PRPs from another earlier or later event, potentiation of a third pathway around the same time may trigger sufficient competition to prevent persistent potentiation on all pathways. Varying the timing of the potentiation of this third pathway enabled one or more pathways to persist whereas others do not. Thus, when the number of competing potential memories increases and the availability of PRPs is limited, a "winner-take-all" scenario appears to prevail whereby some traces persist in a stable manner whereas others do not. The use of multiple pathways models the likely situation in real life when the encoding of multi...

No abstract

Activity-dependent synaptic plasticity is widely accepted to be the cellular correlate of learning and memory. It is believed that associativity between different synaptic inputs can transform short-lasting forms of synaptic plasticity (<3 h) to long-lasting ones. Synaptic tagging and capture (STC) might be able to explain this heterosynaptic support, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms responsible for the synthesis of plasticity-related proteins (PRPs). STC initiate storage processes only when the strength of the synaptic tag and the local concentration of essential proteins are above a certain plasticity threshold. We present evidence that priming stimulation through the activation of metabotropic glutamate receptors substantially increases the "range of threshold" for functional plasticity by producing protein kinase Mζ (PKMζ) as a PRP through local protein synthesis. In addition, our results implicate BDNF as a PRP which is mandatory for establishing cross-capture between synaptic strengthening and weakening, whereas the newly generated PKMζ specifically establishes synaptic tagging of long-term potentiation. Most intriguingly, we show here that STC are confined to specific dendritic compartments and that these compartments contain "synaptic clusters" with different plasticity thresholds. Our results suggest that within a dendritic compartment itself a homeostatic process exists to adjust plasticity thresholds. The range in which these clusters operate can be altered by processes of metaplasticity, which will operate on the cluster independently of other clusters at the same dendrite. These clusters will then prepare the synaptic network to form long-term memories.

The tuberal nucleus (TN) is a surprisingly understudied brain region. We found that somatostatin (SST) neurons in the TN, which is known to exhibit pathological or cytological changes in human neurodegenerative diseases, play a crucial role in regulating feeding in mice. GABAergic tuberal SST (SST) neurons were activated by hunger and by the hunger hormone, ghrelin. Activation of SST neurons promoted feeding, whereas inhibition reduced it via projections to the paraventricular nucleus and bed nucleus of the stria terminalis. Ablation ofSST neurons reduced body weight gain and food intake. These findings reveal a previously unknown mechanism of feeding regulation that operates through orexigenic SST neurons, providing a new perspective for understanding appetite changes.