Proceedings of The Physiological Society
Cardiff University (2009) Proc Physiol Soc 17, C09
Acceleration of ocular dominance plasticity by H-Ras activation in developing visual cortex
C. E. Cheetham1, M. Kaneko2, A. J. Silva3, M. P. Stryker2, K. D. Fox1
1. School of Biosciences, Cardiff University, Cardiff, United Kingdom. 2. Department of Physiology, UCSF, San Fransisco, California, United States. 3. Department of Neurobiology, Psychology, Psychiatry and the Brain Research Institute, UCLA, Los Angeles, California, United States.
H-Ras/extracellular signal-related kinase (ERK) signaling has been shown to modulate hippocampal learning and plasticity (1). ERK signalling has also been implicated in both ocular dominance plasticity and long-term potentiation (LTP) in developing visual cortex (2).To investigate the role of H-Ras in plasticity in developing visual cortex, we used transgenic mice expressing constitutively active H-Ras (H-RasG12V) at levels similar to endogenous H-Ras. We examined the effects of monocular deprivation (MD) on responses in primary visual cortex (V1) during the critical period for ocular dominance plasticity (postnatal day 24-30) using chronic intrinsic signal imaging. Monocular deprivation (3) was performed by suturing the right eye shut under isoflurane anaesthesia (3% in O2). For imaging (4), mice were anaesthetised with isoflurane (0.8% in O2) and 25μg chlorprothixene I.M. We used repeated measures ANOVAs to assess longitudinal changes and one-way ANOVAs to compare genotypes. During MD in wild-type (WT) mice (n=5), an initial depression of closed eye responses is evident after 3 days (-28±3%, mean±S.E.M., P<0.001), followed by a delayed increase in open eye responses after 6 days (+36±2%, P<0.001). In H-Ras mice (n=6), depression of closed eye responses was comparable to that in WT mice after 3 days’ MD (-26±4, P>0.05), but plasticity of open eye responses was dramatically accelerated, showing a large increase after 3 days’ MD (+20±3%, P<0.001 vs baseline, P<0.05 vs WT). To investigate the cellular mechanisms underlying this accelerated plasticity, we made whole cell recordings from layer 2/3 (L2/3) pyramidal neurons in V1 in acute brain slices. LTP at L4 to L2/3 synapses was enhanced in H-Ras mice: mean LTP magnitude 1 hour post-induction was 11±1% in WT and 56±13% in H-Ras mice (P=0.046, t-test, n=15/group). L4 to L2/3 synapses also showed greater short-term facilitation in H-Ras mice (paired pulse ratio (PPR): 1.02±0.03 in WT, 1.22±0.05 in H-Ras, P=0.002, t-test, n=20/group). Moreover, 1 hour after LTP induction, PPR was decreased significantly in H-Ras mice (from 1.42±0.08 to 1.15±0.04, P=0.001) but not in WT mice (from 1.25±0.06 to 1.23±0.12, P=0.69, paired t-tests), suggesting that altered presynaptic release at least partially accounts for enhanced LTP. Therefore, we directly compared presynaptic release probability in H-Ras and WT mice using the rate of use-dependent blockade of NMDARs (N-methyl-D-aspartate receptors) by MK-801. NMDARs blocked more slowly in H-Ras than WT mice (55±15 vs 16±5 trials to reach 50% block, P=0.026, t-test, n=10/group), indicating that release probability is lower in H-Ras mice. Our data indicate that H-Ras activation reduces presynaptic release probability at developing visual cortex synapses. This may underlie the enhanced LTP and accelerated ocular dominance plasticity that we describe.
Where applicable, experiments conform with Society ethical requirements