Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice.

Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion

Brief dark exposure restored ocular dominance plasticity in aging mice and after a cortical stroke

In the primary visual cortex (V1), monocular deprivation (MD) induces a shift in the ocular dominance (OD) of binocular neurons towards the open eye (Wiesel and Hubel, 1963; Gordon and Stryker, 1996). In V1 of C57Bl/6J mice, this OD-plasticity is maximal in juveniles, declines in adults and is absent beyond postnatal day (PD) 110 (Lehmann and Lowel, 2008) if mice are raised in standard cages. Since it was recently shown that brief dark exposure (DE) restored OD-plasticity in young adult rats (PD70-100) (He et al., 2006), we wondered whether DE would restore OD-plasticity also in adult and old mice and after a cortical stroke. To this end, we raised mice in standard cages until adulthood and transferred them to a dark room for 10-14 days. Using intrinsic signal optical imaging we demonstrate that short-term DE can restore OD-plasticity after MD in both adult (PD138) and old mice (PD535), and that OD-shifts were mediated by an increase of open eye responses in V1. Interestingly, restored OD-plasticity after DE was accompanied by a reduction of both parvalbumin expressing cells and perineuronal nets and was prevented by increasing intracortical inhibition with diazepam. DE also maintained OD-plasticity in adult mice (PD150) after a stroke in the primary somatosensory cortex. In contrast, short-term DE did not affect basic visual parameters as measured by optomotry. In conclusion, short-termDEwas able to restore OD-plasticity in both adult and aging mice and even preserved plasticity after a cortical stroke, most likely mediated by reducing intracortical inhibition. (C) 2014 The Authors. Published by Elsevier Inc

The experience-enabled enhancement of the optomotor reflex of the open eye after monocular deprivation (MD) was compromised in both PT-lesioned PSD-95 WT and PSD-95 KO mice.

<p>In contrast, enhancements of spatial vision were present in nonlesioned PSD-95 WT and PSD-95 KO mice. (A, B) Spatial frequency threshold of the optomotor response of the open eye in cycles per degree (cyc/deg) plotted against days after MD. After 7 days of MD, nonlesioned PSD-95 KO mice (A) as well as sham-treated control mice (B; data from Greifzu et al., 2011) showed a significant increase in the spatial frequency threshold of the optomotor reflex of the open eye. This experience-enabled increase was abolished by a PT in S1 (A, B). (C-F) Contrast sensitivity thresholds of the optomotor reflex of the open eye at 6 different spatial frequencies before (day 0) and 7 days after MD. For both nonlesioned PSD-95 KO (C) and PSD-95 WT mice (D), there was an increase in contrast sensitivity after 7 days of MD. After PT, this experience-enabled increase was absent in both groups (E, F).</p

Location of the photothrombotically induced cortical stroke lesion in a PSD-95 KO mouse in S1 (PT, red dashed line).

<p>(A) Top view of a representative mouse brain illustrating the lesion location in S1, on average 1 mm anterior to the anterior border of the primary visual cortex (V1, blue dashed line). (B) Nissl-stained frontal section through the lesion (same animal as in A). (C) Higher magnification composite image of the superficial vascular pattern of the brain and the superimposed optically recorded retinotopic map of the binocular part of V1 of a PSD-95 KO mouse in which the PT-lesion (L) was very close to V1; nevertheless, OD-plasticity was present in this animal (average ODI = 0.00). Scale bar all, 1 mm.</p

In adult PSD-95 KO mice, ocular dominance plasticity was preserved after a PT-stroke in S1.

<p>Optically recorded activity maps of the contralateral (contra) and ipsilateral (ipsi) eye in the binocular region of mouse primary visual cortex (V1) in PT-lesioned PSD-95 WT (A) and PSD-95 KO mice (B) after monocular deprivation (MD), and their quantification (C, D). Open and closed eyes indicated by a white or black circle. (A, B) Grayscale coded response magnitude maps of the contra- and ipsilateral eye (including average V1-activation of the illustrated example) and the histogram of OD-scores including the average OD-index (top row), color-coded polar maps of retinotopy and 2-dimensional OD-maps after MD (lower row) are illustrated. (A) In PSD-95 WT littermates, activity patches evoked by stimulation of the contralateral eye were darker than those of the ipsilateral eye, the average ODI was positive, and warm colors prevailed in the OD-maps, indicating contralateral dominance. In contrast, in PSD-95 KO mice, the contra- and ipsilateral eye activated V1 about equally strong, colder colors appeared in the OD-map, and the histogram of OD-scores shifted to the left (B). Scale bar: 1 mm. (C) Optically imaged OD-indices in PT-lesioned PSD-95 WT and PSD-95 KO mice (light red and red triangles). For comparison, ODIs of control (sham-treated) and PT-lesioned Bl6/J mice are illustrated (white and grey squares). Symbols represent ODI values of individuals, means are marked by horizontal lines. (D) V1-activation elicited by stimulation of the contralateral (C) or ipsilateral (I) eye in PSD-95 WT and PSD-95 KO mice after PT and MD. Note that V1-activtation after stimulation of the contra- and ipsilateral eye was not different in PSD-95 KO mice, indicating preserved juvenile-like OD-plasticity in V1 despite the S1-lesion.</p

Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism

Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment in vivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons