Tea

NMDA receptor-independent LTP in area CA1 can also be induced using tetraethylammonium (TEA+) ion application, a form of LTP that is referred to as LTPk (15, 16). TEA+ is a nonspecific potassium channel blocker, the application of which greatly increases membrane excitability. Like 200-Hz LTP, LTPK is insensitive to NMDA receptor antagonists and is blocked by blockade of voltage-sensitive calcium channels. Moreover, LTPK is blocked by postsynaptic calcium chelator

FIGURE 13 Examples of NMDA receptor-independent LTP. (A) 200-Hz stimulation in area CA1 elicits LTP even in the presence of the NMDA receptor antagonist APV. Data courtesy of Ed Weeber. (B) LTP at Mossy Fiber inputs into area CA3 is also NMDA receptor independent - the potentiation shown occurred in the presence of blockers of the NMDA receptor. Data courtesy of Rick Gray. Reproduced with permission from Kapur et al. (19). (C) Similarly, application of the K channel blocker Tetra-Ethyl Ammonium (TEA) also elicits NMDA receptor-independent LTP in area CA1. Data courtesy of Craig Powell (Ph.D. thesis pg 50; Powell et al. JBC 1994(16)).

FIGURE 13 Examples of NMDA receptor-independent LTP. (A) 200-Hz stimulation in area CA1 elicits LTP even in the presence of the NMDA receptor antagonist APV. Data courtesy of Ed Weeber. (B) LTP at Mossy Fiber inputs into area CA3 is also NMDA receptor independent - the potentiation shown occurred in the presence of blockers of the NMDA receptor. Data courtesy of Rick Gray. Reproduced with permission from Kapur et al. (19). (C) Similarly, application of the K channel blocker Tetra-Ethyl Ammonium (TEA) also elicits NMDA receptor-independent LTP in area CA1. Data courtesy of Craig Powell (Ph.D. thesis pg 50; Powell et al. JBC 1994(16)).

injection as well. One twist is that the induction of LTPK is dependent on synaptic activity, as its induction is blocked by AMPA receptor antagonists. Similar to 200Hz LTP, the current model for TEA LTP is that synaptic depolarization via AMPA receptor activation, augmented by the hyperexcitable membrane owing to K+ channel blockade, leads to a relatively large and prolonged membrane depolarization. This leads to the triggering of LTP through postsynaptic calcium influx.

C. Mossy Fiber LTP in Area CA3

The predominant model system for studying NMDA receptor-independent LTP is not the Schaffer-collateral synapses, but rather the mossy fiber inputs into area CA3 pyramidal neurons. Considerable excitement accompanied the discovery of NMDA receptor-independent LTP at these synapses by Harris and Cotman (17). The mossy fiber synapses are unique, large synapses with unusual presynaptic specializations, and there has been much interest in comparing the attributes and mechanisms of induction of mossy fiber LTP (MF-LTP) with those of NMDA receptor-dependent LTP in area CA1.

However, subsequent progress in investigating the mechanistic differences between these two types of LTP has been relatively slow for several reasons. First, the experiments are technically difficult physiologically—the CA3 region is "finicky,"

and typically area CA3 is the first part of the hippocampal slice preparation to die in vitro. The local circuitry in area CA3 is complex, with many recurrent excitatory connections between neurons there: synapses that also are plastic and exhibit NMDA receptor-dependent LTP. Most problematic has been that there has been an ongoing controversy about the necessity of postsynaptic events, especially elevations of postsynaptic calcium, for the induction of mossy fiber LTP. There basically are two schools of thought on mossy fiber LTP. One line of thinking is that MF-LTP is entirely presynaptic in its induction and expression (18). A second line of thinking is that MF-LTP has a requirement for postsynaptic signal transduction events for its induction (see for example references 19 and 20). The most prominent data supporting the second line of thinking comes from the laboratory of my colleague and collaborator, Dan Johnston. Thus, I cannot pretend to be unbiased in my thinking on this issue. For my purposes in this book, which focuses on NMDA receptor-dependent forms of LTP, I will simply note that this has been an area of controversy.

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