Sensory driven activity during early life is critical for setting up the proper connectivity of the sensory cortices. We ask here whether social play behavior, a particular form of social interaction that is highly abundant during postweaning development, is equally important for setting up connections in the developing prefrontal cortex (PFC). Young male rats were deprived from social play with peers during the period in life when social play behavior normally peaks [postnatal day 21–42] (SPD rats), followed by resocialization until adulthood. We recorded synaptic currents in layer 5 cells in slices from medial PFC of adult SPD and control rats and observed that inhibitory synaptic currents were reduced in SPD slices, while excitatory synaptic currents were unaffected. This was associated with a decrease in perisomatic inhibitory synapses from parvalbumin-positive GABAergic cells. In parallel experiments, adult SPD rats achieved more reversals in a probabilistic reversal learning (PRL) task, which depends on the integrity of the PFC, by using a more simplified cognitive strategy than controls. Interestingly, we observed that one daily hour of play during SPD partially rescued the behavioral performance in the PRL, but did not prevent the decrease in PFC inhibitory synaptic inputs. Our data demonstrate the importance of unrestricted social play for the development of inhibitory synapses in the PFC and cognitive skills in adulthood and show that specific synaptic alterations in the PFC can result in a complex behavioral outcome.SIGNIFICANCE STATEMENTThis study addressed the question whether social play behavior in juvenile rats contributes to functional development of the prefrontal cortex (PFC). We found that rats that had been deprived from juvenile social play (social play deprivation - SPD) showed a reduction in inhibitory synapses in the PFC and a simplified strategy to solve a complex behavioral task in adulthood. Providing one daily hour of play during SPD partially rescued the cognitive skills in these rats, but did not prevent the reduction in PFC inhibitory synapses. Our results demonstrate a key role for unrestricted juvenile social play in PFC development and emphasize the complex relation between PFC circuit connectivity and cognitive function.

Background Neurons in the supragranular layers of the somatosensory cortex integrate sensory (bottom-up) and cognitive/perceptual (top-down) information as they orchestrate communication across cortical columns. It has been inferred, based on intracellular recordings from juvenile animals, that supragranular neurons are electrically mature by the fourth postnatal week. However, the dynamics of the neuronal integration in adulthood is largely unknown. Electrophysiological characterization of the active properties of these neurons throughout adulthood will help to address the biophysical and computational principles of the neuronal integration. Findings Here, we provide a database of whole-cell intracellular recordings from 315 neurons located in the supragranular layers (L2/3) of the primary somatosensory cortex in adult mice (9–45 weeks old) from both sexes (females, N = 195; males, N = 120). Data include 361 somatic current-clamp (CC) and 476 voltage-clamp (VC) experiments, recorded using a step-and-hold protocol (CC, N = 257; VC, N = 46), frozen noise injections (CC, N = 104) and triangular voltage sweeps (VC, 10 (N = 132), 50 (N = 146) and 100 ms (N = 152)), from regular spiking (N = 169) and fast-spiking neurons (N = 66). Conclusions The data can be used to systematically study the properties of somatic integration and the principles of action potential generation across sexes and across electrically characterized neuronal classes in adulthood. Understanding the principles of the somatic transformation of postsynaptic potentials into action potentials will shed light onto the computational principles of intracellular information transfer in single neurons and information processing in neuronal networks, helping to recreate neuronal functions in artificial systems.

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex (mPFC) in rats. When these effects of play experience exactly occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the mPFC and the orbitofrontal cortex (OFC). We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42) and adult (P85) rats after social play deprivation (SPD; between P21-P42). The development of these PFC subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was multiple times higher in the OFC than in the mPFC. SPD did not affect excitatory currents, but reduced inhibitory transmission in both mPFC and OFC. Intriguingly, the reduction occurred in the mPFC during SPD, while the reduction in the OFC only became manifested after SPD. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions.

denotes equal contribution; Correspondence and requests for materials should be addressed to celikel@neurophysiology.nl Magnetic neuromodulation has outstanding promise for the development of novel neural interfaces without direct physical intervention with the brain. Here we tested the utility of Magneto in the adult somatosensory cortex by performing whole-cell intracellular recordings in vitro and extracellular recordings in freely moving mice. Results show that magnetic stimulation does not alter subthreshold membrane excitability or contribute to the generation of action potentials in virally transduced neurons expressing Magneto. Recently introduced Magneto (Wheeler et al., 2016) might provide the highly sought after neuromagnetic actuation in a cell-targeted manner. Some of the excitement about Magneto originates from its design which is comprised of a calcium-permeable non-selective cation channel (Transient receptor potential cation channel subfamily V member 4, TRPV4) fused to the paramagnetic protein ferritin (Wheeler et al., 2016) . This single-construct approach provides a simplified mean for magnetic intervention with neuronal activity.Here, we used lentiviral delivery of Magneto linked to mCherry (Magneto2.0-P2A-mCherry), expressed under the control of ubiquitin promoter for >2 weeks (Fig.1a) before observing and interfering with neural activity (see Methods online), and after confirming successful cleavage of Magneto from mCherry (Suppl. Fig.2a-3) and the subcellular analysis of the expressed protein localization (Suppl. Fig.2b) in a neuronal cell line . Chronic extracellular recordings in freely moving mice (Allen et al., 2003;Celikel et al., 2004;Clem et al., 2008) with 15 tetrodes enabled high-density sampling of neural activity in the vicinity of transduced cells, and yielded well-isolated (Suppl. Fig.4) , stable units (Fig.1b) . Comparison of firing rates within cells across magnetic stimulus conditions (off vs on) showed that magnetic stimulation does not alter the rate of action potentials (APs; Fig.1c ); neither does it modulate the inter-spike interval within cells, nor spike-timing across single units recorded from the same tetrode (Suppl. Fig.5,6) . The lack of spiking was not because neurons could not

Magnetic neuromodulation has outstanding promise for the development of novel neural interfaces without direct physical intervention with the brain. Here we tested the utility of Magneto in the adult somatosensory cortex by performing whole-cell intracellular recordings in vitro and extracellular recordings in freely moving mice. Results show that magnetic stimulation does not alter subthreshold membrane excitability or contribute to the generation of action potentials in virally transduced neurons expressing Magneto.Recently introduced Magneto (Wheeler et al., 2016) might provide the highly sought after neuromagnetic actuation in a cell-targeted manner. Some of the excitement about Magneto originates from its design which is comprised of a calcium-permeable non-selective cation channel (Transient receptor potential cation channel subfamily V member 4, TRPV4) fused to the paramagnetic protein ferritin (Wheeler et al., 2016) . This single-construct approach provides a simplified mean for magnetic intervention with neuronal activity.Here, we used lentiviral delivery of Magneto linked to mCherry (Magneto2.0-P2A-mCherry), expressed under the control of ubiquitin promoter for >2 weeks (Fig. 1a) before observing and interfering with neural activity (see Methods online), and after confirming successful cleavage of Magneto from mCherry (Suppl.Fig. 2a-3) and the subcellular analysis of the expressed protein localization (Suppl.Fig. 2b) in a neuronal cell line . Chronic extracellular recordings in freely moving mice (Allen et al., 2003; Celikel et al., 2004; Clem et al., 2008) with 15 tetrodes enabled high-density sampling of neural activity in the vicinity of transduced cells, and yielded well-isolated (Suppl.Fig. 4) , stable units (Fig. 1b) . Comparison of firing rates within cells across magnetic stimulus conditions (off vs on) showed that magnetic stimulation does not alter the rate of action potentials (APs; Fig. 1c ); neither does it modulate the inter-spike interval within cells, nor spike-timing across single units recorded from the same tetrode (Suppl.Fig. 5,6) . The lack of spiking was not because neurons could not 1