Biology subjects

Bayer, K. U.

Publications and source records attributed to Bayer, K. U..

4 recordsLinked to original sources

bioRxiv2022

CaMKII binding to GluN2B flips a β-adrenergic switch from synaptic depression to potentiation

Learning, memory and cognition are thought to require forms of synaptic plasticity such as hippocampal long-term potentiation and depression (LTP and LTD), and such plasticity can be modulated by {beta}-adrenergic stimulation with isoproterenol or norepinephrine. For instance, LTP versus LTD is induced by high-versus low-frequency stimulation (HFS versus LFS) but, stimulating {beta}-adrenergic receptors ({beta}ARs) enables LTP induction also by LFS. In contrast to HFS-LTP, such {beta}AR-LTP requires signaling by L-type voltage-gated Ca2+-channels, not NMDA-type glutamate receptors (NMDARs). Surprisingly, we found that {beta}AR-LTP still required a non-ionotropic NMDAR function: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, {beta}-adrenergic stimulation with isoproterenol transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, isoproterenol enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased SEP-GluA1 surface expression. Like for the {beta}AR-LTP in hippocampal slices, the effects of isoproterenol on CaMKII movement and SEP-GluA1 surface expression involved L-type Ca2+-channels. Taken together, these results indicate that isoproterenol transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode. One Sentence SummaryBuonarati et al. show that {beta}-adrenergic stimulation enables LTP induction in response to LTD stimuli by switching synaptic CaMKII movement to LTP mode.

neuroscience↗

bioRxiv2022

Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

neuroscience↗

bioRxiv2021

Hippocampal-prefrontal theta coupling develops as mice become proficient in associative odorant discrimination learning

Learning and memory requires coordinated activity between different regions of the brain. Here we studied the interaction between infralimbic medial prefrontal cortex (mPFC) and hippocampal dorsal CA1 during associative odorant discrimination learning in the male mouse. We found that as the animal learns to discriminate odorants in a go- no go task the coupling of high frequency neural oscillations to the phase of theta oscillations (theta-referenced phase-amplitude coupling or tPAC) changes in a manner that results in divergence between rewarded and unrewarded odorant-elicited changes in the theta-phase referenced power (tPRP) for beta and gamma oscillations. In addition, in the proficient animal there was a decrease in the coordinated oscillatory activity between CA1 and mPFC in the presence of the unrewarded odorant. Furthermore, the changes in tPAC resulted in a marked increase in the accuracy for decoding contextual odorant identity from tPRP when the animal became proficient. Finally, we studied the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a protein involved in learning and memory, in oscillatory neural processing in this task. We find that the accuracy for decoding the contextual odorant identity from tPRP decreases in CaMKII knockout mice and that this accuracy correlates with behavioral performance. These results implicate a role for tPAC and CaMKII genotype in olfactory go-no go associative learning in the hippocampal-prefrontal circuit. Significance statementCoupling of neural oscillations between hippocampal CA1 and medial prefrontal cortex (mPFC) is involved in spatial learning and memory, but the role of oscillation coupling for other learning tasks is not well understood. Here we performed local field potential recording in CA1 and mPFC in mice learning to differentiate rewarded from unrewarded odorants in an associative learning task. We find that odorant-elicited changes in the power of bursts of gamma oscillations at distinct phases of theta oscillations become divergent as the animal becomes proficient allowing decoding of contextual odorant identity. Finally, we find that the accuracy to decode contextual odorant identity decreases in mice deficient for the expression of Ca2+/calmodulin-dependent protein kinase II , a protein involved in synaptic plasticity.

neuroscience↗

bioRxiv2021

Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly

Neuronal CaMKII holoenzymes (- and {beta}-isoforms) enable molecular signal computation underlying learning and memory, but also mediate excitotoxic neuronal death. Here, we provide a comparative analysis of these signaling devices, using single particle EM in combination with biochemical and live-cell imaging studies. In the basal state, both isoforms assembled mainly as 12-mers (but also 14-mers, and even 16-mers for the {beta}-isoform). CaMKII and {beta}-isoforms adopted an ensemble of extended activatable states (with average radius of 12.6 versus 16.8 nm, respectively), characterized by multiple transient intra- and inter-holoenzyme interactions associated with distinct functional properties. The extended state of CaMKII{beta} allowed EM analysis to directly resolve intra-holoenzyme kinase-domain dimers that could enable the cooperative activation mechanism by calmodulin, which was found for both isoforms. Surprisingly, high-order CaMKII clustering mediated by inter-holoenzyme kinase-domain dimerization was reduced for the {beta} isoform for both basal and excitotoxicity-induced clusters, both in vitro and in neurons.

molecular biology↗