Programmed cell death widely but heterogeneously affects the developing brain, causing the loss of up to 50% of neurons in rodents. However, whether this heterogeneity originates from neuronal identity and/or network-dependent processes is unknown. Here, we report that the primary motor cortex (M1) and primary somatosensory cortex (S1), two adjacent but functionally distinct areas, display striking differences in density of apoptotic neurons during the early postnatal period. These differences in rate of apoptosis negatively correlate with region-dependent levels of activity. Disrupting this activity either pharmacologically or by electrical stimulation alters the spatial pattern of apoptosis and sensory deprivation leads to exacerbated amounts of apoptotic neurons in the corresponding functional area of the neocortex. Thus, our data demonstrate that spontaneous and periphery-driven activity patterns are important for the structural and functional maturation of the neocortex by refining the final number of cortical neurons in a region-dependent manner.

Key points• Synaptic plasticity between primary nociceptors and second order dorsal horn neurons serves key roles in pain and analgesia • A contribution of NMDA receptors to long-term potentiation and long-term depression at these synapses has been demonstrated before, but much less is known about a possible role of endocannabinoids and cannabinoid (CB) 1 receptors.• Here we show that CB 1 receptors residing on the spinal terminals of primary nociceptors critically contribute to an NMDA receptor-independent form of long-term depression at these synapses, which requires simultaneous pre-and postsynaptic activity.• A similar long-lasting depression of nociceptive signal transmission can also be obtained with application of CB 1 receptor agonists in the presence of presynaptic stimulation alone.• These findings identify a previously unknown form of long-term depression at spinal nociceptor synapses, which may be important for our understanding of pain-related neural plasticity and analgesic actions of CB 1 receptor agonists.Abstract Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB) 1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long-term depression (LTD) of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB 1 receptor-deficient mice (CB 1 −/− mice and sns-CB 1 −/− mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB 1 receptor antagonist AM 251 and mimicked by pharmacological activation of CB 1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB 1 receptors in CB 1 −/− and sns-CB 1 −/− mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB 1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hitherto unknown function of CB 1 receptors in primary nociceptors. Both findings may have important Ako Kato and Pradeep Punnakkal contributed equally to this work.

SUMMARYPurpose: Despite the consistent observation that c-aminobutyric acid A (GABA A ) receptors mediate excitatory responses at perinatal stages, the role of the GABAergic system in the generation of neonatal epileptiform activity remains controversial. Therefore, we analyzed whether tonic and phasic GABAergic transmission had differential effects on neuronal excitability during early development. Methods: We performed whole cell patch-clamp and field potential recordings in the CA3 region of hippocampal slices from immature (postnatal day 4-7) rats to analyze the effect of specific antagonists and modulators of tonic and phasic GABAergic components on neuronal excitability. Key Findings: The GABAergic antagonists gabazine (3 lM) and picrotoxin (100 lM) induced epileptiform discharges, whereas activation of GABA A receptors attenuated epileptiform discharges. Under low-Mg 2+ conditions, 100 nM gabazine and 1 lM picrotoxin were sufficient to provoke epileptiform activity in 63.2% (n = 19) and 53.8% (n = 26) of the slices, respectively. Whole-cell patchclamp experiments revealed that these concentrations significantly reduced the amplitude of phasic GABAergic postsynaptic currents but had no effect on tonic currents. In contrast, 1-lM 4,5,6,7-tetrahydroisoxaz-olo[5,4-c]-pyridin-3-ol (THIP) induced a tonic current of )12 ± 2.5 pA (n = 6) and provoked epileptiform discharges in 57% (n = 21) of the slices. Significance: We conclude from these results that in the early postnatal rat hippocampus a constant phasic synaptic activity is required to control excitability and prevent epileptiform activity, whereas tonic GABAergic currents can mediate excitatory responses. Pharmacologic intervention at comparable human developmental stages should consider these ambivalent GABAergic actions.

Key pointsr Taurine has a pro-and anticonvulsive effect on the immature hippocampus, depending on the dose.r The taurine effect is mediated by GABA A and glycine receptors. r The taurine effect can be partially mimicked by glycine. r Inhibition of glycine receptors has a weak proconvulsive effect on the immature hippocampus. r We conclude that an endogenous activation of glycine receptors by glycine or taurine contributed to the control of neuronal excitability in the immature hippocampus.Abstract While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4-7) rat using field potential recordings. Bath application of 100 μM taurine or 10 μM glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 μM 4-aminopyridine in low Mg 2+ solution. This proconvulsive effect was prevented by 3 μM strychnine or after incubation with the loop diuretic bumetanide (10 μM), suggesting that it required glycine receptors and an active NKCC1-dependent Cl − accumulation. Application of higher doses of taurine (ࣙ1 mM) or glycine (100 μM) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABA A receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 μM) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro-and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus.R. Chen and A. Okabe contributed equally to this publication.

Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNA s that are required to modify synaptic functions. Despite the well‐known role of RNA ‐binding proteins ( RBP s) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage‐inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long‐term potentiation are strongly impaired in Gadd45a ‐deficient mice, a phenotype accompanied by reduced levels of memory‐related mRNA s. The majority of the Gadd45α ‐ regulated transcripts show unusually long 3′ untranslated regions (3′ UTR s) that are destabilized in Gadd45a ‐deficient mice via a transcription‐independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory‐related mRNA s. Our study reveals a new function for extended 3′ UTR s in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.