Michael Köhl

Distinct roles of GABA(A) and GABA(B) receptors in balancing and terminating persistent cortical activity.

Cortical networks spontaneously fluctuate between persistently active Up states and quiescent Down states. The Up states are maintained by recurrent excitation within local circuits, and can be turned on and off by synaptic input. GABAergic inhibition is believed to be important for stabilizing such persistent activity by balancing the excitation, and could have an additional role in terminating the Up state. Here, we report that GABAA and GABAB receptor-mediated inhibition have distinct and complementary roles in balancing and terminating persistent activity. In a model of Up–Down states expressed in slices of rat entorhinal cortex, the GABAA receptor antagonist, gabazine (50–500 nm), concentration-dependently decreased Up state duration, eventually leading to epileptiform bursts. In contrast, the GABAB receptor antagonist, CGP55845 (50 nm to 1 μm), increased the duration of persistent network activity, and prevented stimulus-induced Down state transitions. These results suggest that while GABAA receptor-mediated inhibition is necessary for balancing persistent activity, activation of GABAB receptors contributes to terminating Up states.

Amphiphilic Porphyrins for Second Harmonic Generation Imaging

Amphiphilic donor-acceptor meso-ethynyl porphyrins with polar pyridinium electron-acceptor head groups and hydrophobic dialkyl-aniline electron donors have high molecular hyperpolarizabilities (as measured by hyper-Rayleigh scattering) and high affinities for biological membranes. When bound to water droplets in dodecane, or to the plasma membranes of living cells, they can be used for second harmonic generation (SHG) microscopy; an incident light of wavelength 840 nm generates a strong frequency-doubled signal at 420 nm. Copper(II) and nickel(II) porphyrin complexes give similar SHG signals to those of the free-base porphyrins, while exhibiting no detectable two-photon excited fluorescence.

Aberration-free three-dimensional multiphoton imaging of neuronal activity at kHz rates

Multiphoton microscopy is a powerful tool in neuroscience, promising to deliver important data on the spatiotemporal activity within individual neurons as well as in networks of neurons. A major limitation of current technologies is the relatively slow scan rates along the z direction compared to the kHz rates obtainable in the x and y directions. Here, we describe a custom-built microscope system based on an architecture that allows kHz scan rates over hundreds of microns in all three dimensions without introducing aberration. We further demonstrate how this high-speed 3D multiphoton imaging system can be used to study neuronal activity at millisecond resolution at the subcellular as well as the population level.

The Roles of GABAB Receptors in Cortical Network Activity

Temporally-structured cortical activity in the form of synchronized network oscillations and persistent activity is fundamental for cognitive processes such as sensory processing, motor control, working memory, and consolidation of long-term memory. The roles of fast glutamatergic excitation via AMPA, kainate, and NMDA receptors, as well as fast GABAergic inhibition via GABA(A) receptors, in such network activity have been studied in great detail. In contrast, we have only recently begun to appreciate the roles of slow inhibition via GABA(B) receptors in the control of cortical network activity. Here, we provide a framework for understanding the contributions of GABA(B) receptors in helping mediate, modulate, and moderate different types of physiological and pathological cortical network activity. We demonstrate how the slow time course of GABA(B) receptor-mediated inhibition is well suited to help mediate the slow oscillation, to modulate the power and spatial profile of gamma oscillations, and to moderate the relative spike timing of individual neurons during theta oscillations. We further suggest that GABA(B) receptors are interesting therapeutic targets in pathological conditions where cortical network activity is disturbed, such as epilepsy and schizophrenia.

Left–right dissociation of hippocampal memory processes in mice

Significance The hippocampus is implicated in memory and spatial navigation. In rodents, in which this bilateral brain structure has been studied extensively, the left and right hippocampi have generally been considered functionally equivalent. However, recent work has revealed unexpected asymmetries in the molecular and morphological characteristics of neuronal connections according to brain hemisphere. To investigate whether this left–right difference has implications for hippocampal function, we acutely inhibited activity in an area-specific and genetically-defined population of hippocampal neurons during various behavioral tasks. We found that silencing the CA3 area of the left hippocampus impaired associative spatial long-term memory, whereas the equivalent manipulation in the right hippocampus did not. Thus, our data show that hippocampal long-term memory processing is lateralized in mice. Left–right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3–CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left–right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left–right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.

Hemisphere-specific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity

Postsynaptic spines at CA3-CA1 synapses differ in glutamate receptor composition according to the hemispheric origin of CA3 afferents. To study the functional consequences of this asymmetry, we used optogenetic tools to selectively stimulate axons of CA3 pyramidal cells originating in either left or right mouse hippocampus. We found that left CA3 input produced more long-term potentiation at CA1 synapses than right CA3 input as a result of differential expression of GluN2B subunit–containing NMDA receptors.

Critical Behavior of a Trapped Interacting Bose Gas

The phase transition of Bose-Einstein condensation was studied in the critical regime, where fluctuations extend far beyond the length scale of thermal de Broglie waves. We used matter-wave interference to measure the correlation length of these critical fluctuations as a function of temperature. Observations of the diverging behavior of the correlation length above the critical temperature enabled us to determine the critical exponent of the correlation length for a trapped, weakly interacting Bose gas to be ν = 0.67 ± 0.13. This measurement has direct implications for the understanding of second-order phase transitions.

Presynaptic induction and expression of timing-dependent long-term depression demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist.

NMDA receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). To help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. We used this method to investigate timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.

Superfluid to Mott insulator transition in one, two, and three dimensions

No HeadingWe have created one-, two-, and three-dimensional quantum gases and study the superfluid to Mott insulator transition. Measurements of the transition using Bragg spectroscopy show that the excitation spectra of the low-dimensional superfluids differ significantly from the three-dimensional case.

Caged intracellular NMDA receptor blockers for the study of subcellular ion channel function.

We have previously synthesized a caged form of the use-dependent N-methyl-D-aspartate (NMDA) receptor ion channel blocker MK801 and used intracellular photolysis of this compound to demonstrate the subcellular location of NMDA receptor ion channels involved in synaptic plasticity. Here, we discuss considerations regarding the choice of caging molecule, synthesis and the potential uses for caged ion channel blockers in neurophysiology.