Journal of Integrative Neuroscience

Learning, memory and long-term potentiation (LTP) are supported by factors including post-synaptic calcium ion flux activating and transforming the hexagonal calcium-calmodulin kinase II (CaMKII) holoenzyme. Upon calcium-induced activation, up to six kinase domains extend upward, and up to six kinase domains extend downward from the CaMKII association domain, the fully activated holoenzyme resembling a robotic insect 20 nanometers in length. Each extended kinase domain can be phosphorylated, and able to phosphorylate other proteins, thus potentially further encoding synaptic information at intraneuronal molecular sites for memory storage, processing and distribution. Candidate sites for phosphorylation-encoded molecular memory include microtubules, cylindrical lattice polymers of the protein tubulin. Using molecular modeling, we find spatial dimensions and geometry of the six extended CaMKII kinase domains can precisely match those of microtubule hexagonal lattice neighborhoods (both A- and B-lattices), and show two feasible phosphorylation mechanisms. In one, phosphorylation sites (e.g., valine 208) on a CaMKII extended kinase domain interact with serine 444 on a C-terminal "tail" of tubulin. In the second, the CaMKII kinase domain unfurls, enabling phosphorylation sites to contact threonine and serine sites on the tubulin surface. We suggest sets of six CaMKII kinase domains phosphorylate hexagonal microtubule lattice neighborhoods collectively, e.g., conveying synaptic information as ordered arrays of six "bits", and thus a "byte", with (minimally) 2⁶ (64) possible bit states per CaMKII-microtubule interaction. We model two levels of interaction between CaMKII and microtubules, suggesting a testable framework for molecular memory encoding.

Vascular dementia is one of the most important causes that account for 20–40% of all dementia cases. The aim of this study was to investigate whether electroacupuncture can reduce behavior deficit and long-term potentiation (LTP) in vascular dementia. Here we used a middle cerebral artery occlusion (MCAo) technique to induce a vascular dementia model with additional electroacupuncture (EA) manipulation. Behaviors were impaired in animals with MCAo, and similar results were observed with long-term potentiation induction. MCAo decreased the expression of LTP from 180.4±14.9% to 112.5±18.3%, suggesting that cerebral ischemia could impair the hippocampal LTP. In addition, immunostaining results showed that the expressions of N-methyl-D-aspartate receptor subtype 1 (NR1) and transient receptor potential vanilloid subtype 1 (TRPV1) receptors were significantly increased in the hippocampal CA1 areas. Noticeably, these phenomena can be reversed by 2 Hz EA at Baihui acupoint (GV20) for six consecutive days. Our results support a rescue role of 2 Hz EA for MCAo-induced behavior and LTP impairment. These results also suggest that NMDAR1 and TRPV1 may be involved in this pathway.

A reaction-diffusion model is presented to encapsulate calcium-induced calcium release (CICR) as a potential mechanism for somatofugal bias of dendritic calcium movement in starburst amacrine cells. Calcium dynamics involves a simple calcium extrusion (pump) and a buffering mechanism of calcium binding proteins homogeneously distributed over the plasma membrane of the endoplasmic reticulum within starburst amacrine cells. The system of reaction-diffusion equations in the excess buffer (or low calcium concentration) approximation are reformulated as a nonlinear Volterra integral equation which is solved analytically via a regular perturbation series expansion in response to calcium feedback from a continuously and uniformly distributed calcium sources. Calculation of luminal calcium diffusion in the absence of buffering enables a wave to travel at distances of 120 μm from the soma to distal tips of a starburst amacrine cell dendrite in 100 msec, yet in the presence of discretely distributed calcium-binding proteins it is unknown whether the propagating calcium wave-front in the somatofugal direction is further impeded by endogenous buffers. If so, this would indicate CICR to be an unlikely mechanism of retinal direction selectivity in starburst amacrine cells.

Optical imaging of dendritic calcium signals provided evidence of starburst amacrine cells exhibiting calcium bias to somatofugal motion. In contrast, it has been impractical to use a dual-patch clamp technique to record membrane potentials from both proximal dendrites and distal varicosities of starburst amacrine cells in order to unequivocally prove that they are directionally sensitive to voltage, as was first suggested almost two decades ago. This paper aims to extend the passive cable model to an active cable model of a starburst amacrine cell that is intrinsically dependent on the electrical properties of starburst amacrine cells, whose various macroscopic currents are described quantitatively. The coupling between voltage and calcium just below the membrane results in a voltage-calcium system of coupled nonlinear Volterra integral equations whose solutions must be integrated into a prescribed model for example, for a synaptic couplet of starburst amacrine cells. Networks of starburst amacrine cells play a fundamental role in the retinal circuitry underlying directional selectivity. It is suggested that the dendritic plexus of starburst amacrine cells provides the substrate for the property of directional selectivity, while directional selectivity is a property of the exclusive layerings and confinement of their interconnections within the sublaminae of the inner plexiform layer involving cone bipolar cells and directionally selective ganglion cells.

In this paper, we found that spatial and temporal asymmetricity of excitatory connections are able to generate directional selectivity which can be enhanced by asymmetrical inhibitory connections by reconstructing a hexagonally-arranged three-layered simulation model of retina by NEURON simulator. Asymmetric excitatory inputs to ganglion cells with randomly arborizing dendrites were able to generate weaker directional selectivity to moving stimuli whose speed was less than 10 μm/msec. By just adding asymmetric inhibitory connections via inhibitory amacrine cells, directional selectivity became stronger to respond to moving stimuli at ten times faster speed (< 100 μm/msec). In conclusion, an excitatory mechanism appeared to generate directional selectivity while asymmetric inhibitory connections enhance directional selectivity in retina.