Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex.

The NMDA receptor (NMDAR) is a heteromer comprised of NR1 and NR2 subunits. Mice that overexpress the NR2B subunit exhibit enhanced hippocampal LTP, prolonged NMDAR currents, and improved memory ( Tang et al., 1999). In the current study, we explored visual cortex plasticity and NMDAR function in NR2B overexpressing transgenic mice. Unlike the hippocampus, in vitro synaptic plasticity of the visual cortex was unaltered by NR2B overexpression. Consistent with the plasticity findings, NMDAR excitatory postsynaptic current (EPSC) durations from layer 2/3 pyramidal cells were similar in wild-type (wt) and transgenic (tg) mice. Furthermore, temporal summation of NMDAR EPSCs to 10, 20, and 40 Hz stimulation did not differ between cells from wt and tg mice. Finally, although in situ studies clearly demonstrate overexpression of NR2B mRNA in visual cortex, we failed to observe a significant elevation in the synaptic expression of NR2B protein. We conclude that the synaptic ratio of NR2B over NR2A in the NMDA receptor complex in the visual cortex is not significantly influenced by the transgene overexpression. These data suggest that mRNA availability is not a limiting factor for the synthesis of NR2B protein in the visual cortex, and support the hypothesis that levels of NR2A, rather than NR2B, normally determine the subunit composition of NMDARs in visual cortex.

Induction of NMDA receptor-dependent long-term depression in visual cortex does not require metabotropic glutamate receptors.

We tested the role of group I mGluRs in the induction of long-term depression (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI hydrolysis in visual cortical synaptoneurosomes, and that it effectively antagonizes the actions of the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices. However, LY341495 has no effect on the induction of LTD by low-frequency stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent LTD. These results indicate that group I mGluR activation is not required for the induction of NMDA receptor-dependent LTD in the visual cortex.

Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex.

The effects of brain-derived neurotrophic factor (BDNF) were investigated on synaptic transmission and two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in visual cortex slices prepared from young (P21 -28) rats. The slices treated for 2-5 h in BDNF showed no difference from control slices when a 'strong' tetanus was used (theta-burst stimulation) to elicit a maximal level of LTP but displayed significantly greater synaptic potentiation in response to a 'weak' (20 Hz) tetanus. The BDNF-treated slices also showed significantly less LTD in response to a 1 Hz tetanus. Thus, BDNF treatment alters the relationship between stimulation frequency and synaptic plasticity in the visual cortex, shifting the modification threshold to the left. The effects of BDNF on LTP and LTD induction may be attributed to the significant enhancement of synaptic responses that was observed during conditioning stimulation. These data suggest that one role of BDNF during development of the visual cortex may be to modulate the properties of synaptic plasticity, enhancing synaptic strengthening and reducing synaptic weakening processes which contribute to the formation of specific synaptic connections.

Effects of the metabotropic glutamate receptor antagonist MCPG on phosphoinositide turnover and synaptic plasticity in visual cortex.

The neurotransmitter glutamate, in addition to activating ligand-gated ion channels, also stimulates phosphoinositide (PI) hydrolysis in neurons by activating a group of G-protein-coupled metabotropic glutamate receptors (mGluRs). A role for mGluRs in synaptic plasticity originally was hypothesized based on the observation that the developmental decline in glutamate-stimulated PI turnover is well correlated with the decline in experience-dependent synaptic plasticity in visual cortex. Over the past few years, the compound alpha-methyl-4-carboxyphenylglycine (MCPG) has been widely used to test the role of PI-coupled mGluRs in a number of types of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), ocular dominance plasticity in visual cortex, and the neural plasticity underlying learning and memory. The conclusions of most of these studies were based on the assumption that MCPG blocks the actions of glutamate at PI-coupled mGluRs in the cerebral cortex. Here we show that this assumption is not valid in visual cortex. Although MCPG does antagonize the actions of the synthetic mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid, it fails to block PI turnover and changes in spike adaptation stimulated by glutamate, the endogenous mGluR ligand. In addition, we find that MCPG fails to block the NMDA receptor-dependent forms of LTP, LTD, and depotentiation in visual cortex.