Bhalla, U. S. | bioRxiv Science

bioRxiv2018

Subunit exchange enhances information retention by CaMKII in dendritic spines

Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. CaMKII is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different microenvironments, the Post Synaptic Density (PSD) and spine cytosol. We show that in the PSD, subunit exchange leads to coordinated switching and prolongs state stability of the fraction of CaMKII that is present in clusters; and underlies spreading of activation among the remaining CaMKII that is uniformly distributed. Subunit exchange increases the robustness of the CaMKII switch measured as range of bistability both with respect to protein phosphatase 1 (PP1) levels and protein turnover rates. In the phosphatase-rich spine cytosol, subunit exchange leads to slower decay of activity following calcium stimuli. We find that subunit exchange can explain two time-courses of CaMKII activity decay observed in recent experiments monitoring endogenous activity of CaMKII in the spine. Overall, CaMKII exhibits multiple timescales of activity in the synapse and subunit exchange enhances the information retention ability of CaMKII by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks.\n\nSignificance StatementDespite everyday forgetfulness, we can recall some memories years after they were formed. How are we able to protect some memories for so long? Previous work has shown that the abundant brain protein Calcium/calmodulin dependent protein Kinase II (CaMKII) can form a very stable binary switch which can store information for years. Building on this work, we analyzed the implications of a recently discovered phenomenon of subunit exchange on the state switching properties of CaMKII. In subunit exchange fragments of one CaMKII molecule detatch and exchange with another. We discovered that this improves the information retention ability of CaMKII both in the context where it stores information for long times, and also where it integrates information over the timescale of minutes.

neuroscience↗

bioRxiv2017

Precise excitation-inhibition balance controls gain and timing in hippocampus

Excitation-inhibition (EI) balance controls excitability, dynamic range, and input gating in many brain circuits. Subsets of synaptic input can be selected or gated by precise modulation of finely tuned EI balance, but assessing the granularity of EI balance requires combinatorial analysis of excitatory and inhibitory inputs. Using patterned optogenetic stimulation of hippocampal CA3 neurons, we show that hundreds of unique CA3 input combinations recruit excitation and inhibition with a nearly identical ratio, demonstrating precise EI balance at the hippocampus. Crucially, the delay between excitation and inhibition decreases as excitatory input increases from a few synapses to tens of synapses. This creates a dynamic millisecond-range window for postsynaptic excitation, controlling membrane depolarization amplitude and timing via subthreshold divisive normalization. We suggest that this combination of precise EI balance and dynamic EI delays forms a general mechanism for millisecond-range input gating and subthreshold gain control in feedforward networks.

neuroscience↗

bioRxiv2017

Synaptic input sequence discrimination on behavioral time-scales mediated by reaction-diffusion chemistry in dendrites

Sequences of events are ubiquitous in sensory, motor, and cognitive function. Key computational operations, including pattern recognition, event prediction, and plasticity, involve neural discrimination of spatio-temporal sequences. Here we show that synaptically-driven reaction-diffusion pathways on dendrites can perform sequence discrimination on behaviorally relevant time-scales. We used abstract signaling models to show that this selectivity arises when inputs at successive locations are aligned with, and amplified by, propagating chemical waves triggered by previous inputs. We incorporated biological detail using sequential synaptic input onto spines in morphologically, electrically, and chemically detailed pyramidal neuronal models. Again, sequences were recognized, and local channel modulation on the length-scale of sequence input could elicit changes in neuronal firing. We predict that dendritic sequence-recognition zones occupy 5 to 20 microns and recognize time-intervals of 0.2 to 5s. We suggest that this mechanism provides highly parallel and selective neural computation in a functionally important time range.

neuroscience↗