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Synaptic Tagging and Cross-tagging during LTP and LTD

Short description: Individual synapses or a group of synapses are capable of being modified independently according to the stimulus which they receive. A weak tetanus can induce an early form LTP (early-LTP) lasting 2-3 h, while a strong tetanus can induce a late form of LTP (late-LTP) lasting 6-8 h, the latter of which being dependent on translation and transcription for its persistence. The logical problem arises of how mRNAs or proteins can selectively target synapses that have undergone early-LTP and convert the transient early-LTP to a long lasting late-LTP. The ’synaptic tagging’ hypothesis (Frey & Morris, 1997, 1998) has been put forward as a way to address this problem. According to this hypothesis the persistence of LTP is mediated by the intersection of two dissociable events. The first event involves the generation of a transient local ‘synaptic tag’ at specific synapses in association with the induction of early-LTP. The second involves the production and diffused distribution of ‘plasticity related -proteins’ (PRPs) that are captured and utilized only at those synapses possessing a tag. Recently we have also reported ‘synaptic tagging’ during LTD and have shown a positive associative phenomenon of LTP and LTD which we named ‘cross-tagging’ (Sajikumar.S & Frey.J.U, 2004). Here, process-specific tags can capture process-unspecific PRPs (See Figure.1) (Navakkode et al, 2004, 2005). We also reported that the local ‘tags’ can be reset by depotentiation in a time-dependent manner. (Sajikumar.S & Frey .J.U, 2004). However, the identity of the 'synaptic tag' and its specificity for LTP or LTD remained still elusive even though it was speculated to be either a role of spine morphological changes, kinases like CaMKII, or of the involvement of PKC-isotype: PKMzeta. We have identified PKMzeta as the first LTP specific plasticity related protein, which maintains potentiation but not depression (see Sajikumar et al., 2005)
We use long-term slice incubation and do long-term electrophysiological recordings within hippocampal slices in vitro (up to 14 h, see Sajikumar et al., Curr Opin Neurobiol. 2005), these recordings include extra- and intracellular recordings, patch clamp-techniques and optical methods (2-photon-confocal microscopy) as well as pharmacological interventions.

Role of PKMζ in synaptic tagging and cross-tagging during LTP and LTD in a CA1 pyramidal neuron

Fig. 1 Role of PKMζ in synaptic tagging and cross-tagging during LTP and LTD in a CA1 pyramidal neuron. Hypothesis of the activity-dependent synthesis of a pool of PRPs that are either specific for LTP (red triangles), specific for LTD (blue trapezoids), or non-specific (mixed red and blue trapezoids). PKMζ is the first identified LTP-specific PRP. PDE4B3 is the first known non-specific PRP, which could be also important for process-specific aspects such as the regulation of the synthesis of process-specific PRPs (Ahmed and Frey, 2003; Navakkode et al. 2004; Ahmed at al., 2004). An LTD-specific PRP has yet to be identified. Interestingly, the LTP-specific PRP PKMζ has dual functions - it is required for maintaining LTP and for the induction processes of LTP and LTD (red triangle on the base of the tagged synapse, in which we suppose that PKMζ activity required for the induction of the plastic events does not require de-novo synthesis of the molecule). We suggest that not only does the process-specific tag consist of a complex machinery of molecules specific for LTP (red symbol at the synapse) or LTD (blue symbol at the synapse) (Frey and Morris, 1998; Sajikumar and Frey, 2004), but also PRPs represent a pool of proteins expressing their effector roles by selective interactions with these process-specific tag complexes, in addition to basic short-term plasticity functions. D1 - dopaminergic D1/D5-receptor; Glu- glutamatergic synapse.

Applied methods:

  • long-term incubation and electrophysiological recordings of hippocampal slices in vitro (> 10h)  
  • conventional electrophysiological recording techniques (extra- and intracellular recordings, patch clamp-techniques)
  • optical methods (2-photon-confocal microscopy; Calcium-Imaging using conventional fluorescence techniques and confocal microscopy)  

Structural Reinforcement of early-LTP in hippocampus of freely moving rats.

Short description: In the hippocampus of freely moving rats different form of long-term potentiation can be induced by different stimulation protocols. So a so called weak tetanus applied to the perforant pathway induced a early-LTP in the dentate gyrus, which lasts about 4 to 6 h after its induction. This form of LTP is independent on protein synthesis and independent on activation of heterosynaptic inputs to the DG. The maintenance of the E-LTP can be influenced, when distinct brain structures (e.g. basolateral amygdala, locus coeruleus or medial septum) are electrically stimulated in a distinct time window arround the induction of E-LTP. This so called structural reinforcement is dependent on heterosynaptic innervation and can be blocked, when the stimulation of the modulating structure is performed under influence of an inhibitor of protein synthesis.

Example for influence of electrical stimulation of the basolateral amygdala on maintenance of E-LTP in the dentate gyrus induced by tetanisation of the perforant pathway.

Fig. 1: Example for influence of electrical stimulation of the basolateral amygdala on maintenance of E-LTP in the dentate gyrus induced by tetanisation of the perforant pathway.
Reinforcement of hippocampal early-LTP by stimulation of the basolateral nucleus of the amygdala (BLA) in freely moving rats.
Left: Schematic illustration of electrode localization. For clarity, in this section the DG stimulation electrode is shown activating the perforant pathway (broken line). Originally, this electrode was positioned in the angular bundle. Insets show analog examples of recordings obtained before (dotted line) and after (filled line) LTP induction of the perforant path (top left) and after stimulation of the BLA (top right).
Right: Induction of early-LTP by a weak tetanus of the perforant path (open circles) shows a characteristical decay of LTP to baseline within 5 to 6 h after its induction. When the BLA is electrically stimulated within a distinct time window (up to half an hour before or after tetanisation of the perforant pathway) this E-LTP can be reinforced into longlasting form of LTP, which lasts at least 8 h (right up, filled circles). The stimulation of the BLA outside of this time window failed to reinforce E-LTP in dentate gyrus (button right).

Applied methods:

  • conventional substance-application techniques and electrophysiological recordings in vivo (freely moving animals, use of osmotic mini pumps, etc.) 

We are interested in mechanisms of reinforcement of hippocampal LTP within the dentate gyrus (DG) and the CA1 area, the consolidation of cellular memory processes, and possible parallel consolidation processes of spatial memories either by emotional challenges in novel environments (e.g. swim stress) or by mastering a cognitive task (spatial learning). The studies focus on the identification of task-specific neuromodulatory heterosynaptic and hormonal activations and their influences on either cellular signaling processes and behavior. DG-LTP-reinforcement by spatial training depends on the specific constraints of the learning paradigm. During holeboard training LTP-reinforcement is related to the formation of a lasting reference memory, whereas during water-maze training cognitive aspects interfere with emotionally challenging components. Thus, different spatial-learning tasks are weighted distinctly by the animal and result in the activation of different cellular signaling pathways, indicating that aspects of specific learning paradigms such as shifts of attention and emotional content directly influence functional plasticity and memory formation.

Behavioral reinforcements

Applied methods:

  • Electrophysiological recording in vivo in freely moving animals
  • Application of pharmacological substances
  • Microdialysis in freely moving and learning animals
  • HPLC
  • Proteinbiochemistry
  • Spatial and contextual learning (water maze, holeboard, radial maze, Barnes maze, shuttle box)
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