SUMMARY Production of reactive oxygen species (ROS) increases with neuronal activity that accompanies synaptic development and function. Transcription-related factors and metabolic enzymes that are expressed in all tissues have been described to counteract neuronal ROS to prevent oxidative damage. Here, we describe the antioxidant gene LanCL1 that is prominently enriched in brain neurons. Its expression is developmentally regulated and induced by neuronal activity, neurotrophic factors implicated in neuronal plasticity and survival, and oxidative stress. Genetic deletion of LanCL1 causes enhanced accumulation of ROS in brain, and development-related lipid, protein, and DNA damage, mitochondrial dysfunction and apoptotic neurodegeneration. LanCL1 transgene protects neurons from ROS. LanCL1 protein purified from eukaryotic cells catalyzes the formation of thioether products similar to glutathione S-transferase. These studies reveal a neuron-specific glutathione defense mechanism that is essential for neuronal function and survival.

It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc−/− cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc−/−, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.

Summary GABAergic activity is important in neocortical development and plasticity. Since the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show by laser-scanning photostimulation that layer 4 and layer 5 GABAergic interneurons in auditory cortex in neonatal mice (< P7) receive extensive translaminar glutamatergic input via NMDAR-only synapses. Extensive translaminar AMPAR-mediated input developed during the second postnatal week while NMDAR-only presynaptic connections decreased. GABAergic interneurons showed two spatial patterns of translaminar connection: inputs originating predominantly from supragranular or from supragranular and infragranular layers including subplate which relays early thalamocortical activity. Sensory deprivation altered the development of translaminar inputs. Thus, distinct translaminar circuits to GABAergic interneurons exist throughout development and the maturation of excitatory synapses is input specific. Glutamatergic signaling from subplate and intracortical sources likely plays a role in the maturation of GABAergic interneurons.

The thalamocortical circuit is of central importance in relaying information to the cortex. In development, subplate neurons (SPNs) form an integral part of the thalamocortical pathway. These early born cortical neurons are the first neurons to receive thalamic inputs and excite neurons in the cortical plate. This feed-forward circuit topology of SPNs supports the role of SPNs in shaping the formation and plasticity of thalamocortical connections. Recently it has been shown that SPNs also receive inputs from the developing cortical plate and project to the thalamus. The cortical inputs to SPNs in early ages are mediated by N-methyl-D-aspartate (NMDA)-receptor only containing synapses while at later ages α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptors are present. Thus, SPNs perform a changing integrative function over development. NMDA-receptor only synapses are crucially influenced by the resting potential and thus insults to the developing brain that causes depolarizations, e.g., hypoxia, can influence the integrative function of SPNs. Since such insults in humans cause symptoms of neurodevelopmental disorders, NMDA-receptor only synapses on SPNs might provide a crucial link between early injuries and later circuit dysfunction. We thus here review subplate associated circuits, their changing functions, and discuss possible roles in development and disease.

The development of GABAergic interneurons is important for the functional maturation of cortical circuits. After migrating into the cortex, GABAergic interneurons start to receive glutamatergic connections from cortical excitatory neurons and thus gradually become integrated into cortical circuits. These glutamatergic connections are mediated by glutamate receptors including AMPA and NMDA receptors and the ratio of AMPA to NMDA receptors decreases during development. Since previous studies have shown that retinal input can regulate the early development of connections along the visual pathway, we investigated if the maturation of glutamatergic inputs to GABAergic interneurons in the visual cortex requires retinal input. We mapped the spatial pattern of glutamatergic connections to layer 4 (L4) GABAergic interneurons in mouse visual cortex at around postnatal day (P) 16 by laser-scanning photostimulation and investigated the effect of binocular enucleations at P1/P2 on these patterns. Gad2-positive interneurons in enucleated animals showed an increased fraction of AMPAR-mediated input from L2/3 and a decreased fraction of input from L5/6. Parvalbumin-expressing (PV) interneurons showed similar changes in relative connectivity. NMDAR-only input was largely unchanged by enucleation. Our results show that retinal input sculpts the integration of interneurons into V1 circuits and suggest that the development of AMPAR- and NMDAR-only connections might be regulated differently.