Prog Brain Res. period. When assayed at P14, after focal arborization has been established, the effect disappeared. Conversely, chronic NMDA treatment, known to induce functional synaptic depressive disorder in the sSC, decreased retinocollicular synapse density at P14, but not earlier, during the refinement period (P8). Thus during the development of retinocollicular topographic order, there is a period when NMDAR activity predominantly eliminates retinal axon synapses. Levamlodipine besylate We were able to extend this period by using retinal lesions to reduce synaptic density in a defined zone. Synapse density on intact retinocollicular axons sprouting into this zone was increased by NMDAR blockade, even when examined at P14. Thus, the period of NMDAR-dependent synaptic destabilization is usually terminated by a factor related to the density and refinement of retinal arbors. have not been performed. We examined synapse formation by RGC axons in sSC during and after the period of axon terminal refinement. The emergence of dense, topographically appropriate retinal axon terminal arbors occurs in the rat sSC between post-natal day (P)4 and P12 by the exuberant elaboration of arbors, and their elimination from incorrect regions (Simon and O’Leary, 1992). Retinal axons can develop gross topographic order in the absence of retinal activity (O’Leary and Cowan, 1983), through positional cues provided by gradients of membrane bound guidance molecules (O’Leary et al., 1999). However, correlated RGC activity is also necessary for refinement of the retinal axon arbors into focused terminations. This activity is usually provided by spontaneous waves of depolarization driven by cholinergic retinal amacrine cells (Feller et al., 1996), and later through glutamatergic synapses (Wong et al., 2000). The early cholinergic waves appear particularly important. 2 cholinergic receptor knockout mice do not have these waves, though their Levamlodipine besylate RGCs are still spontaneously active. These animals develop axon arbors that are more dispersed and less dense than wild type (Bansal et al., 2000; McLaughlin et al., 2003). The ectopic terminals of these mice remain even after normal photoreceptor driven activity develops (~P8CP11). NMDAR blockade also prevents the removal of ectopic retinal arbors from topographically inappropriate locales in the developing sSC (Simon et al., 1992), although the development of clumped ipsilateral axons restricted to the stratum opticum is not disrupted (Colonnese and Constantine-Paton, 2001). NMDAR currents are normally down-regulated by increases in retinal activity coincident with the end of retinotopic map refinement (Shi et al., 1997; Shi et al., 2000; Townsend et al., 2004), suggesting that this regulation of the NMDAR current may play a role in the termination of the period for topographic mapping. Studies in some systems have suggested that initial synapse formation is usually a trial and error process in which the NMDAR is one of the primary determinants of synaptic stability (Rajan et al., 1999b), while other systems have indicated that this receptor can also be a determinant of synaptic elimination (Schmidt et al., 2000). To discriminate among these possibilities as the basis of the NMDAR-dependent refinement in the sSC, we have here quantitatively examined retinocollicular synapse density following chronic NMDAR antagonist or agonist treatment during, and shortly after, the period of topographic refinement. If NMDAR-dependent refinement is usually predominantly a result of stabilizing synapses, blockade of the receptor should decrease retinal Levamlodipine besylate terminal synapse density; conversely, Levamlodipine besylate if early NMDAR activation is usually primarily Rabbit polyclonal to CCNB1 destabilizing synapses, blockade should increase retinal terminal synapse density. These experiments incorporate the assumption that synaptic weakening and destabilization leads to synapse loss. This can be tested using the agonist treatment. Chronic NMDA treatment induces synaptic depressive disorder in the sSC (Shi et al., 2001; Zhao and Constantine-Paton, 2002). Consequently, if functional depression is associated with a loss of synapses, this treatment should decrease retinal terminal synapse density. We have previously used lesion-induced sprouting of the ipsilateral projection to provide information on the relationship between NMDAR activity, synapse.