John E. Lisman

The molecular basis of CaMKII function in synaptic and behavioural memory

Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.

The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory

In this article we develop the concept that the hippocampus and the midbrain dopaminergic neurons of the ventral tegmental area (VTA) form a functional loop. Activation of the loop begins when the hippocampus detects newly arrived information that is not already stored in its long-term memory. The resulting novelty signal is conveyed through the subiculum, accumbens, and ventral pallidum to the VTA where it contributes (along with salience and goal information) to the novelty-dependent firing of these cells. In the upward arm of the loop, dopamine (DA) is released within the hippocampus; this produces an enhancement of LTP and learning. These findings support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.

Bursts as a unit of neural information: making unreliable synapses reliable

Several lines of evidence indicate that brief (< 25 ms) bursts of high-frequency firing have special importance in brain function. Recent work shows that many central synapses are surprisingly unreliable at signaling the arrival of single presynaptic action potentials to the postsynaptic neuron. However, bursts are reliably signaled because transmitter release is facilitated. Thus, these synapses can be viewed as filters that transmit bursts, but filter out single spikes. Bursts appear to have a special role in synaptic plasticity and information processing. In the hippocampus, a single burst can produce long-term synaptic modifications. In brain structures whose computational role is known, action potentials that arrive in bursts provide more-precise information than action potentials that arrive singly. These results, and the requirement for multiple inputs to fire a cell suggest that the best stimulus for exciting a cell (that is, a neural code) is coincident bursts.

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro

In standard protocols, the frequency of synaptic stimulation determines whether CA1 hippocampal synapses undergo long-term potentiation or depression. Here we show that during cholinergically induced theta oscillation (theta) synaptic plasticity is greatly sensitized and can be induced by a single burst (4 pulses, 100 Hz). A burst given at the peak of theta induces homosynaptic LTP; the same burst at a trough induces homosynaptic LTD of previously potentiated synapses. Heterosynaptic LTD is produced at inactive synapses when others undergo LTP. The synaptic modifications during theta require NMDA receptors and muscarinic receptors. The enhancement is cooperative and occludes with standard LTP. These results suggest that the similar bursts observed during theta rhythm in vivo may be a natural stimulus for inducing LTP/LTD.

Mechanisms of CaMKII action in long-term potentiation

Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.

The Theta-Gamma Neural Code

Theta and gamma frequency oscillations occur in the same brain regions and interact with each other, a process called cross-frequency coupling. Here, we review evidence for the following hypothesis: that the dual oscillations form a code for representing multiple items in an ordered way. This form of coding has been most clearly demonstrated in the hippocampus, where different spatial information is represented in different gamma subcycles of a theta cycle. Other experiments have tested the functional importance of oscillations and their coupling. These involve correlation of oscillatory properties with memory states, correlation with memory performance, and effects of disrupting oscillations on memory. Recent work suggests that this coding scheme coordinates communication between brain regions and is involved in sensory as well as memory processes.Theta and gamma frequency oscillations occur in the same brain regions and interact with each other, a process called cross-frequency coupling. Here, we review evidence for the following hypothesis: that the dual oscillations form a code for representing multiple items in an ordered way. This form of coding has been most clearly demonstrated in the hippocampus, where different spatial information is represented in different gamma subcycles of a theta cycle. Other experiments have tested the functional importance of oscillations and their coupling. These involve correlation of oscillatory properties with memory states, correlation with memory performance, and effects of disrupting oscillations on memory. Recent work suggests that this coding scheme coordinates communication between brain regions and is involved in sensory as well as memory processes.

A Model of Synaptic Memory: A CaMKII/PP1 Switch that Potentiates Transmission by Organizing an AMPA Receptor Anchoring Assembly

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is localized in the postsynaptic density (PSD) and is necessary for LTP induction. Much has been learned about the autophosphorylation of CaMKII and its dephosphorylation by PSD protein phosphatase-1 (PP1). Here, we show how the CaMKII/PP1 system could function as an energy-efficient, bistable switch that could be activated during LTP induction and remain active despite protein turnover. We also suggest how recently discovered binding interactions could provide a structural readout mechanism: the autophosphorylated state of CaMKII binds tightly to the NMDAR and forms, through CaMKII-actinin-actin-(4.1/SAP97) linkages, additional sites for anchoring AMPARs at synapses. The proposed model has substantial experimental support and elucidates principles by which a local protein complex could produce stable information storage and readout.

A role for NMDA-receptor channels in working memory

The NMDA class of glutamate receptors has a critical role in the induction of long-term potentiation (LTP), a synaptic modification that may encode some forms of long-term memory. However, NMDA-receptor antagonists disrupt a variety of mental processes that are not dependent on long-term memory. For example, they interfere with working memory, a short-lasting form of memory that is maintained by neuronal activity rather than by synaptic modification. This suggests that there are unknown functions of the NMDA-receptor channel. One hint is that in addition to producing the calcium entry important for LTP induction, NMDA-receptor channels produce voltage-dependent excitatory postsynaptic potentials (EPSPs). Here, we use a network model to show that such NMDA-receptor-mediated EPSPs could be critical in maintaining working memory. These results provide a mechanistic framework useful in understanding dopamine-NMDA interactions in working memory and the disruption of working memory in schizophrenia.

A Neural Coding Scheme Formed by the Combined Function of Gamma and Theta Oscillations

Brain oscillations are important in controlling the timing of neuronal firing. This process has been extensively analyzed in connection with gamma frequency oscillations and more recently with respect to theta frequency oscillations. Here we review evidence that theta and gamma oscillations work together to form a neural code. This coding scheme provides a way for multiple neural ensembles to represent an ordered sequence of items. In the hippocampus, this coding scheme is utilized during the phase precession, a phenomenon that can be interpreted as the recall of sequences of items (places) from long-term memory. The same coding scheme may be used in certain cortical regions to encode multi-item short-term memory. The possibility that abnormalities in theta/gamma could underlie symptoms of schizophrenia is discussed.