Slaying the metabolic syndrome. Are we battling the Hydra or the Chimera?

Metabolic syndrome is the latest moniker for an alliance of pathologic conditions that conspire to amplify the risk of atherosclerosis or type 2 diabetes. Several recent advances in the understanding of this condition have led to its widespread adoption in clinical practice, prompted by influential practice guidelines. In particular, guidelines relating to the management of hyperlipidemia and hypertension afford a prominent role for metabolic syndrome, as a risk factor and a target of therapy. In many ways, the scientific evidence base has not kept pace with the demand for treatment options, rendering therapy nebulous. Most prominently, we do not know whether to adopt a strategy based on a multi-pronged attack, or whether to concentrate our greatest efforts on attacking a critical weakness. We review the limited data available regarding metabolic syndrome, with a focus on expert opinion gleaned from clinical guidelines, and offer advice to the clinician from our own experience with this population.

Imaging parallel fiber and climbing fiber responses and their short-term interactions in the mouse cerebellar cortex in vivo.

A major question in the study of cerebellar cortical function is how parallel fiber and climbing fiber inputs interact to shape information processing. Emphasis has been placed on the long-term effects due to conjunctive stimulation of climbing fibers and parallel fibers. Much less emphasis has been placed on short-term interactions and their spatial nature. To address this question the responses to parallel fiber and climbing fiber inputs and their short-term interaction were characterized using optical imaging with Neutral Red in the anesthetized mouse in vivo. Electrical stimulation of the cerebellar surface evoked an increase in fluorescence consisting of a transverse optical beam. The linear relationship between the optical responses and stimulus parameters, high spatial resolution and close coupling to the electrophysiological recordings show the utility of this imaging methodology. The majority of the optical response was due to activation of postsynaptic alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors with a minor contribution from the presynaptic parallel fibers. Stimulation of the inferior olive evoked parasagittal bands that were abolished by blocking AMPA glutamate receptors. Conjunctive stimulation of the cerebellar surface and inferior olive resulted in inhibition of the climbing fiber evoked optical responses. This lateral inhibition of the parasagittal bands extended out from both sides of an activated parallel fiber beam and was mediated by GABA(A) but not GABA(B) receptors. One hypothesized role for lateral inhibition of this type is to spatially focus the interactions between parallel fiber and climbing fiber input on Purkinje cells. In summary optical imaging with Neutral Red permitted visualization of cerebellar cortical responses to parallel fiber and climbing fiber activation. The GABA(A) dependent lateral inhibition of the climbing fiber evoked parasagittal bands by parallel fiber stimulation shows that cerebellar interneurons play a short-term role in shaping the responses of Purkinje cells to climbing fiber input.

Role of calcium, glutamate neurotransmission, and nitric oxide in spreading acidification and depression in the cerebellar cortex.

This study investigated the mechanisms underlying the recently reported fast spreading acidification and transient depression in the cerebellar cortex in vivo. Spreading acidification was evoked by surface stimulation in the rat and mouse cerebellar cortex stained with the pH-sensitive dye neutral red and monitored using epifluorescent imaging. The probability of evoking spreading acidification was dependent on stimulation parameters; greater frequency and/or greater amplitude were more effective. Although activation of the parallel fibers defined the geometry of the spread, their activation alone was not sufficient, because blocking synaptic transmission with low Ca(2+) prevented spreading acidification. Increased postsynaptic excitability was also a major factor. Application of either AMPA or metabotropic glutamate receptor antagonists reduced the likelihood of evoking spreading acidification, but stronger stimulation intensities were still effective. Conversely, superfusion with GABA receptor antagonists decreased the threshold for evoking spreading acidification. Blocking nitric oxide synthase (NOS) increased the threshold for spreading acidification, and nitric oxide donors lowered the threshold. However, spreading acidification could be evoked in neuronal NOS-deficient mice (B6;129S-Nos1(tm1plh)). The depression in cortical excitability that accompanies spreading acidification occurred in the presence of AMPA and metabotropic glutamate receptor antagonists and NOS inhibitors. These findings suggest that spreading acidification is dependent on extracellular Ca(2+) and glutamate neurotransmission with a contribution from both AMPA and metabotropic glutamate receptors and is modulated by nitric oxide. Therefore, spreading acidification involves both presynaptic and postsynaptic mechanisms. We hypothesize that a regenerative process, i.e., a nonpassive process, is operative that uses the cortical architecture to account for the high speed of propagation.

Novel form of spreading acidification and depression in the cerebellar cortex demonstrated by neutral red optical imaging.

A novel form of spreading acidification and depression in the rat cerebellar cortex was imaged in vivo using the pH-sensitive dye, Neutral red. Surface stimulation evoked an initial beam of increased fluorescence (i.e., decreased pH) that spread rostrally and caudally across the folium and into neighboring folia. A transient but marked suppression in the excitability of the parallel fiber-Purkinje cell circuitry accompanied the spread. Characteristics differentiating this phenomenon from the spreading depression of Leao include: high speed of propagation on the surface (average of 450 microm/s), stable extracellular DC potential, no change in blood vessel diameter, and repeatability at short intervals. This propagating acidification constitutes a previously unknown class of neuronal processing in the cerebellar cortex.