Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures.
Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. "Autonomous" CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.
Department of Pediatrics, University of Colorado, School of Medicine, CO, USA.
Paul B
PB
Bernard
Department of Pediatrics, University of Colorado, School of Medicine, CO, USA.
Anna M
AM
Castano
Neuroscience Graduate Program, University of Colorado, School of Medicine, CO, USA; Department of Pharmacology, University of Colorado, School of Medicine, CO, USA.
K Ulrich
KU
Bayer
Department of Pediatrics, University of Colorado, School of Medicine, CO, USA; Neuroscience Graduate Program, University of Colorado, School of Medicine, CO, USA; Department of Neurology, University of Colorado, School of Medicine, CO, USA; Department of Pharmacology, University of Colorado, School of Medicine, CO, USA; Department of Otolaryngology, University of Colorado, School of Medicine, CO, USA. Electronic address: tim.benke@ucdenver.edu.
Tim A
TA
Benke
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000503:physiopathology*; D007608:Kainic Acid; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D046509:Tissue Culture Techniques
D020746:Calcium Channels, L-Type; D018094:Receptors, Metabotropic Glutamate; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D007608:Kainic Acid
Autism; CaMKII; Early life seizure; Long-term depression; Metabotropic glutamate receptor; Voltage-gated calcium channels