Peter V. Massey

Differential Roles of NR2A and NR2B-Containing NMDA Receptors in Cortical Long-Term Potentiation and Long-Term Depression

It is widely believed that long-term depression (LTD) and its counterpart, long-term potentiation (LTP), involve mechanisms that are crucial for learning and memory. However, LTD is difficult to induce in adult cortex for reasons that are not known. Here we show that LTD can be readily induced in adult cortex by the activation of NMDA receptors (NMDARs), after inhibition of glutamate uptake. Interestingly there is no need to activate synaptic NMDARs to induce this LTD, suggesting that LTD is triggered primarily by extrasynaptic NMDA receptors. We also find that de novo LTD requires the activation of NR2B-containing NMDAR, whereas LTP requires activation of NR2A-containing NMDARs. Surprisingly another form of LTD, depotentiation, requires activation of NR2A-containing NMDARs. Therefore, NMDARs with different synaptic locations and subunit compositions are involved in various forms of synaptic plasticity in adult cortex.

Long-term depression: multiple forms and implications for brain function

Long-term potentiation (LTP) and long-term depression (LTD) remain widely accepted vertebrate models for the cellular and molecular mechanisms that underlie synaptic changes during learning and memory. Although LTD is a phenomenon that occurs in many regions of the CNS, it is clear that the mechanisms recruited in its induction and expression can vary, depending on many factors, including brain region and developmental time point. LTD in the hippocampus and cerebellum is probably the best characterized, although there are also other brain areas where mechanisms of LTD are well understood, and where it is thought to have a functional role.

Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus

The role of NMDA receptors in the induction of long-term potentiation (LTP) and long-term depression (LTD) is well established but which particular NR2 subunits are involved in these plasticity processes is still a matter of controversy. We have studied the effects of subtype selective NMDA receptor antagonists on LTP induced by high frequency stimulation (100 Hz for 1s) and LTD induced by low frequency stimulation (1 Hz for 15 min) in the CA1 region of hippocampal slices from 14 day old Wistar rats. Against recombinant receptors in HEK293 cells NVP-AAM077 (NVP) was approximately 14-fold selective for NR2A vs NR2B receptors, whilst Ro 25-6981 (Ro) was highly selective for NR2B receptors. On NMDA receptor-mediated EPSCs from Schaffer collaterals in CA1 neurones, NVP and Ro both reduced the amplitude but differentially affected the time constant of decay. The data are compatible with the selective effect of NVP (0.1 microM) and Ro (4 microM) on native NR2A and NBR2B receptors, respectively. NVP reduced both LTP and LTD whereas Ro reduced only LTP. Thus, LTP was reduced by 63% at 0.1 microM NVP and almost completely at 0.4 microM whereas 5 microM Ro reduced LTP by 45%. These data are consistent with a role for both NR2A and NR2B in the induction of LTP, under our experimental conditions. In comparison, LTD was unaffected by Ro (5 microM) even in the presence of a glutamate uptake inhibitor threo-beta-benzylaspartic acid (TBOA) to increase the concentration of glutamate at NR2B containing receptors. NVP (0.2-0.4 microM), however, produced a concentration dependent inhibition of LTD which was complete at 0.4 microM. The lack of effect of 0.1 microM NVP on LTD contrasts with its marked effect on LTP and raises the possibility that different NVP-sensitive NR2 subunit-containing NMDA receptors are required for LTP and LTD in this preparation.

Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory.

We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.

Activation of muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex.

There is strong evidence that decrements in neuronal activation in perirhinal cortex when a novel stimulus is repeated provide a neural substrate of visual recognition memory. There is also strong evidence that muscarinic acetylcholine (ACh) receptors are involved in learning and memory. However, the mechanisms underlying neuronal decrements in the perirhinal cortex and the basis of ACh involvement in learning and memory are not understood. In an in vitro preparation of rat perirhinal cortex we now demonstrate that activation of ACh receptors by carbachol (CCh) produces long‐lasting depression (LLD) of synaptic transmission that is dependent on muscarinic M1 receptor activation. Crucially, the induction of this form of LLD requires neither N‐methyl‐d‐aspartate receptor activation nor synaptic stimulation. CCh‐induced LLD was not blocked by the protein kinase C inhibitors staurosporine or BIM, or by the protein phosphatase inhibitor okadaic acid. However, each of cyclopiazonic acid (an agent that depletes intracellular calcium stores) and anisomycin (an inhibitor of protein synthesis) significantly reduced the magnitude of CCh‐induced LLD. These mechanisms triggered by muscarinic receptor activation could play a role in the induction and/or expression of certain forms of activity‐dependent long‐term depression in perirhinal cortex. An understanding of CCh‐induced LLD may thus provide clues to the mechanisms underlying lasting neuronal decrements that occur in the perirhinal cortex and hence for neural substrates of visual recognition memory.

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.

Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA(A)-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimers disease, but also show how distal changes in plasticity could contribute to diaschisis.

L-Type Voltage-Dependent Calcium Channel Antagonists Impair Perirhinal Long-Term Recognition Memory and Plasticity Processes

The perirhinal cortex of the temporal lobe is essential for the familiarity discrimination component of recognition memory. In view of the importance of changes in calcium ion concentration for synaptic plasticity, the present study examined the effects of L-type voltage-dependent calcium channel (VDCC) antagonism on rat perirhinal-based familiarity discrimination processes and plasticity including long-term depression (LTD), long-term potentiation (LTP), and depotentiation. Single doses of three different types of L-type VDCC antagonists, verapamil, diltiazem, and nifedipine, administered systemically, or verapamil administered locally into the perirhinal cortex, impaired acquisition of long-term (24 h) but not shorter-term (20 min) recognition memory. L-type VDCC antagonism also disrupted memory retrieval after 24 h but not 20 min. Differential neuronal activation produced by viewing novel or familiar visual stimuli was measured by Fos expression. L-type VDCC antagonism by verapamil in perirhinal cortex during memory acquisition disrupted the normal pattern of differential Fos expression, so paralleling the antagonist-induced memory impairment. In slices of perirhinal cortex maintained in vitro, verapamil was without effect on baseline excitability or LTP but blocked LTD and depotentiation. The consistency of effects across the behavioral and cellular levels of analysis provides strong evidence for the involvement of perirhinal L-type VDCCs in long-term recognition memory processes.

Experience-dependent modification of mechanisms of long-term depression

Mechanisms of long-term potentiation and depression (LTP and LTD) change considerably during development, but the importance of these changes and the factors that control them is not clear. We found that visual experience triggered a switch in mechanisms of LTD in rat perirhinal cortex, an area critical for visual recognition memory. Thus, changes in synaptic plasticity mechanisms were correlated with the changing physiological demands on the CNS.

Learning-specific changes in long-term depression in adult perirhinal cortex.

Learning is widely believed to involve synaptic plasticity, using mechanisms such as those used in long-term potentiation (LTP). We assess whether the mechanisms used in alternative forms of plasticity, long-term depression (LTD) and depotentiation, play a role in learning. We have exploited the involvement of the perirhinal cortex in two different forms of learning to compare simultaneously, within the same brain region, their effects on LTD and depotentiation. Multiple-exposure learning but not single-exposure learning in vivo prevented, in a muscarinic receptor-dependent manner, subsequent induction of LTD and depotentiation, but not LTP, in perirhinal cortex in vitro. The contrast in the effects of the two types of learning under these particular experimental conditions indicate that the in vitro change is unlikely to be attributable to synapse-specific plastic changes registering the precise details of the individual learned associations. Instead, it is concluded that the lack of LTD and depotentiation arises from, and establishes the importance of, a learning-related generalized change in plasticity gain. The existence of this additional mechanism has important implications for interpretations of how plasticity relates to learning.