Biomedical subjects

Sreedharan Sajikumar

Publications and source records attributed to Sreedharan Sajikumar.

6 recordsLinked to original sources

PubMed2005

Mitogen-activated protein kinase-mediated reinforcement of hippocampal early long-term depression by the type IV-specific phosphodiesterase inhibitor rolipram and its effect on synaptic tagging.

Rolipram, a selective inhibitor of cAMP-specific phosphodiesterase 4 (PDE4), has been shown to reinforce an early form of long-term potentiation (LTP) to a long-lasting LTP (late LTP). Furthermore, it was shown that the effects of rolipram-mediated reinforcement of LTP interacts with processes of synaptic tagging (Navakkode et al., 2004). Here we show in CA1 hippocampal slices from adult rats in vitro that rolipram also converted an early form of long-term depression (LTD) that normally decays within 2-3 h, to a long-lasting LTD (late LTD) if rolipram was applied during LTD-induction. Rolipram-reinforced LTD (RLTD) was NMDA receptor- and protein synthesis-dependent. Furthermore, it was dependent on the synergistic coactivation of dopaminergic D(1) and D(5) receptors. This let us speculate that RLTD resembles electrically induced, conventional CA1 late LTD, which is characterized by heterosynaptic processes and synaptic tagging. We therefore asked whether synaptic tagging occurs during RLTD. We found that early LTD in an S1 synaptic input was transformed into late LTD if early LTD was induced in a second independent S2 synaptic pathway during the inhibition of PDE by rolipram, supporting the interaction of processes of synaptic tagging during RLTD. Furthermore, application of PD 98059 (2'-amino-3'-methoxyflavone) or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), specific inhibitors of mitogen-activated protein kinases (MAPKs), prevented RLTD, suggesting a pivotal role of MAPK activation for RLTD. This MAPK activation was triggered during RLTD by the synergistic interaction of NMDA receptor- and D(1) and D(5) receptor-mediated Rap/B-Raf pathways, but not by the Ras/Raf-1 pathway in adult hippocampal CA1 neurons, as shown by the use of the pathway-specific inhibitors manumycin (Ras/Raf-1) and lethal toxin 82 (Rap/B-Raf).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

Synaptic tagging and cross-tagging: the role of protein kinase Mzeta in maintaining long-term potentiation but not long-term depression.

Protein kinase Mzeta (PKMzeta) 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 PKMzeta 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 zeta-pseudosubstrate inhibitory peptide. We found that persistent PKMzeta 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 PKMzeta was specific to the tagged synapses. To further delineate the specificity of the function of PKMzeta 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 PKMzeta 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, PKMzeta is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and cross-tagging.

Animals↗

PubMed2005

Protein synthesis-dependent long-term functional plasticity: methods and techniques.

There is growing interest in late-LTP and late-LTD, that is, distinct forms of functional plasticity that require somatic functions such as protein synthesis in addition to the transient synaptic processes that are required for short lasting forms. Interestingly, to date only these forms of lasting plastic events could be detected in healthy, freely moving animals and thus, they are considered as physiological cellular models of learning and memory formation. Late-LTP and -LTD are characterized by 'synaptic tagging' or 'capture' and 'synaptic cross-tagging', but there are only a few laboratories that can currently perform experiments studying these properties. In brain slice work, there are many different approaches to investigate these processes using different methodological variations: some allow slices to rest for long periods before the experiment starts, others do not; some run their experiments at near to physiological temperatures, others at lower temperatures; some stimulate frequently, others do not.

Animals↗

PubMed2004

The type IV-specific phosphodiesterase inhibitor rolipram and its effect on hippocampal long-term potentiation and synaptic tagging.

We investigated the effects of rolipram, a selective cAMP phosphodiesterase (PDE) inhibitor, on late plastic events during functional CA1 plasticity in vitro in rat hippocampal slices. We present data showing that an early form of long-term potentiation (LTP) (early-LTP) that normally decays within 2-3 hr can be converted to a lasting LTP (late-LTP) if rolipram is applied during tetanization. This rolipram-reinforced LTP (RLTP) was NMDA receptor and protein synthesis dependent. cAMP formation in region CA1 during late-LTP requires dopaminergic receptor activity (Frey et al., 1989, 1990). Thus, we studied whether RLTP was influenced by inhibitors of the D(1)/D(5) receptor. Application of the specific D(1)/D(5) antagonist SCH23390 (0.1 microm) did not prevent RLTP, suggesting that the phosphodiesterase inhibitor acts downstream of the D(1)/D(5) receptors. We also studied whether rolipram can interact with processes of synaptic tagging, because RLTP was also dependent on protein synthesis, similar to late-LTP. Inhibition of PDE and subsequent induction of RLTP in one synaptic population were able to transform early-LTP into late-LTP in a second, independent synaptic population of the same neurons. This supports our hypothesis that cAMP-dependent processes are directly involved in the synthesis of plasticity-related proteins.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD.

Protein synthesis-dependent, synapse input-specific late phases of long-term potentiation (LTP) and depression (LTD) may underlie memory formation at the cellular level. Recently, it was described that the induction of LTP can mark a specifically activated synapse by a synaptic tag to capture synapse non-specific plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for prolonged periods. Here we show in rat hippocampal slices in vitro, that the induction of protein synthesis-dependent late-LTD is also characterized by synaptic tagging and that heterosynaptic induction of either LTD or LTP on two sets of independent synaptic inputs S1 and S2 can lead to late-associative interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was sufficient to transform early- into late-LTD in S2 when process-specific synaptic tags were set. We name this new associative property of cellular information processing 'cross-tagging.'

Animals↗

PubMed2003

Anisomycin inhibits the late maintenance of long-term depression in rat hippocampal slices in vitro.

Studies were performed to investigate whether electrically-induced long-term depression (LTD) within rat hippocampal slices in vitro shares any common cellular features with LTD in the intact animal, with particular emphasis being placed on mechanisms required for its late maintenance. Our initial studies have led to the development of stimulation protocols which are able to reliably produce different forms of LTD. Depending on the induction protocol applied, we are able to demonstrate a transient protein synthesis-independent early-LTD with a duration of up to 3-4 h, together with a de novo protein synthesis-dependent late-LTD lasting for at least 8 h. Furthermore, we are able to show input-specific LTD within the CA1 region, with expression shown only by those synapses specifically stimulated by a low-frequency protocol. These studies are important pre-requisites to investigate mechanisms of 'synaptic tagging' and 'late-associativity' during LTD.

Action Potentials↗