Temporal Correlations between Functional and Molecular Changes in NMDA Receptors and GABA Neurotransmission in the Superior Colliculus

Abstract

Activation of the NMDA subtype of glutamate receptor is required for activity-dependent structural plasticity in many areas of the young brain. Previous work has shown that NMDA receptor currents decline approximately at the time that developmental synaptic plasticity ends, and in situ hybridization studies have suggested that receptor subunit changes may be occurring during the same developmental interval. To establish a system in which the relationship between these properties of developing synapses can be explored, we have combined patch-clamp recordings with mRNA-and protein-level biochemical analyses to study the developmental regulation of NMDA receptors in the superficial layers of the rat superior colliculus. These experiments document an abrupt decrease in the NMDA receptor contribution to synaptic currents that occurs before eye opening and is closely associated with changes in NR1 protein, rapidly rising levels of the NMDA receptor subunit NR2A, and decreasing levels of NR2B. The functional and molecular changes also are correlated with the developmental decline in structural plasticity in these layers. In addition, both physiological and biochemical methods show evidence of GABA-mediated inhibition in the superficial collicular layers beginning after eye opening. This may provide an additional heterosynaptic mechanism for controlling excitation and plasticity in this neuropil by pattern vision. Thus our findings lend support to the idea that high levels of NMDA receptor function are associated with the potential for structural rearrangement in CNS neuropil and that the functional downregulation of this molecule results, at least partially, from changes in its subunit composition.

Developmental loss of miniature N -methyl- d -aspartate receptor currents in NR2A knockout mice

“…In WT mice, spontaneous excitatory postsynaptic potentials and spon͞mini NMDARc amplitudes remained constant between P8 and P13 ( Fig. 1 A and B) (2). In this interval spon͞mini NMDARcs in the NR2AKO showed a progressive decay in amplitude terminating at ϳP13, when NMDARcs were indistinguishable from baseline noise (Ͻ3 pA at Ϫ70 mV; Fig.…”

“…Film exposures were in the linear range for all bands being compared. Band density was quantified as described by using NIH IMAGE and its gel-plotting macros (2). At least three separate protein isolations were made at all time points and averaged for quantitation.…”

“…(NMDARs) contain NR1 (GluR 1) plus varying proportions of NR2A (GluR 1) and NR2B (GluR 2) subunits (1,2). The decay times of evoked NMDAR currents (NMDARcs) become faster during development as NR2A is incorporated (3)(4)(5)(6).…”

Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

“…In addition, SC interneurons undergo well characterized and precisely timed developmental changes in synaptic transmission. At the end of the second postnatal week (P13-P14), when visual activity increases with retinal maturation and eye-opening, frequency of spontaneous synaptic activity mediated by AMPARs (sAMPA) and GABA A Rs (sGABA) increases, whereas NMDAR currents (sNMDAs) decay faster because of a change in the composition from NR2B-rich to NR2A-rich receptors (Shi et al, 1997Aamodt et al, 2000;Colonnese et al, 2003;Lu and Constantine-Paton, 2004;Townsend et al, 2004;van Zundert et al, 2004). The dependence of these synaptic changes on neural activity led us to predict that hyperactivity would be associated with accelerated development of synaptic transmission in hSOD1 G93A mice.…”

Inhibitory Plasticity Facilitates Recovery of Stimulus Velocity Tuning in the Superior Colliculus after Chronic NMDA Receptor Blockade

“…Evidence in a number of systems shows that activation of NMDARs can influence the effectiveness of GABAergic inputs. For example, maturation of GABA currents in rat SC may be regulated by NMDAR activity (Shi et al, 1997;Aamodt et al, 2000;Henneberger et al, 2005), and NMDA receptor activation can lead to long-term depression of GABAergic synapses in Xenopus tectum (Lien et al, 2006). Thus, changes in the strength of GABAergic synapses can result from the developmental or experimental modification of NMDAR activity.…”