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Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditional Arc/Arg3.1 knock-out (KO) mice to investigate the causal relationship between Arc/Arg3.1 deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Using in vivo local field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in which Arc/Arg3.1 was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in which Arc/Arg3.1 was deleted during late postnatal development. Our data show that constitutive Arc/Arg3.1 KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal of Arc/Arg3.1 per se does not cause schizophrenia-like behavior. Prenatal or perinatal deletion of Arc/Arg3.1 alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation of Arc/Arg3.1 rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders. SIGNIFICANCE STATEMENT The activity-regulated and memory-linked gene Arc/Arg3.1 has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss of Arc/Arg3.1 can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion of Arc/Arg3.1 before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion of Arc/Arg3.1 does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation of Arc/Arg3.1 might critically imbalance brain networks and lead to emergence of schizophrenia.

Arc/Arg3.1, an activity regulated immediate early gene, is essential for learning and memory, synaptic plasticity, and maturation of neural networks. It has also been implicated in several neurodevelopmental disorders, including schizophrenia. Here, we used male and female constitutive and conditionalArc/Arg3.1knock-out (KO) mice to investigate the causal relationship betweenArc/Arg3.1deletion and schizophrenia-linked neurophysiological and behavioral phenotypes. Usingin vivolocal field potential recordings, we observed dampened oscillatory activity in the prefrontal cortex (PFC) of the KO and early conditional KO (early-cKO) mice, in whichArc/Arg3.1was deleted perinatally. Whole-cell patch-clamp recordings from neurons in PFC slices revealed altered synaptic properties and reduced network gain in the KO mice as possible mechanisms underlying the oscillation deficits. In contrast, we measured normal oscillatory activity in the PFC of late conditional KO (late-cKO) mice, in whichArc/Arg3.1was deleted during late postnatal development. Our data show that constitutiveArc/Arg3.1KO mice exhibit no deficit in social engagement, working memory, sensorimotor gating, native locomotor activity, and dopaminergic innervation. Moreover, adolescent social isolation, an environmental stressor, failed to induce deficits in sociability or sensorimotor gating in adult KO mice. Thus, genetic removal ofArc/Arg3.1 per sedoes not cause schizophrenia-like behavior. Prenatal or perinatal deletion ofArc/Arg3.1alters cortical network activity, however, without overtly disrupting the balance of excitation and inhibition in the brain and not promoting schizophrenia. Misregulation ofArc/Arg3.1rather than deletion could potentially tip this balance and thereby promote emergence of schizophrenia and other neuropsychiatric disorders.SIGNIFICANCE STATEMENTThe activity-regulated and memory-linked geneArc/Arg3.1has been implicated in the pathogenesis of schizophrenia, but direct evidence and a mechanistic link are still missing. The current study asks whether loss ofArc/Arg3.1can affect brain circuitry and cause schizophrenia-like symptoms in mice. The findings demonstrate that genetic deletion ofArc/Arg3.1before puberty alters synaptic function and prefrontal cortex activity. Although brain networks are disturbed, genetic deletion ofArc/Arg3.1does not cause schizophrenia-like behavior, even when combined with an environmental insult. It remains to be seen whether misregulation ofArc/Arg3.1might critically imbalance brain networks and lead to emergence of schizophrenia.

In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.

During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up-regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage.

Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 as a universal switch in migDCs that may be exploited to selectively modify immune responses.

Approximately half the excitatory neurons in layer 6 (L6) of the rat barrel cortex project to the thalamus with axon collaterals ramifying in the granular L4; the remaining project within cortex with collaterals restricted to infragranular laminae. In analogy, L6 inhibitory neurons also include locally arborizing and inter-laminar projecting neurons. We examined whether L6 neurons participating in different laminar interactions were also morphologically and electrically distinct. Corticothalamic (CT) neurons were labeled by in vivo injections of a retrogradely transported fluorescent tracer into the primary thalamic nucleus. Whole cell current-clamp recordings were performed from labeled and unlabeled L6 neurons in brain slices of juvenile rats; the morphology of cells was subsequently recovered and reconstructed. Corticocortical (CC) neurons were distinguished from CT cells based on the absence of a subcortical projection and the predominantly infragranular arborization of their axon collaterals. Two morphological CC subtypes could be further distinguished based on the structure of their apical dendrite. Electrically, CT neurons had shorter membrane time-constants and action potential (AP) durations and higher rheobase currents. CC neurons fired high-frequency spike doublets or triplets on sustained depolarization; the burst frequency also distinguished the two morphological CC subtypes. Among inhibitory L6 cells, the L4-projecting (L6iL4) and local (L6iL6) inhibitory neurons also had contrasting firing properties; L6iL4 neurons had broader APs and lower maximal firing rates. We propose that L6 excitatory and inhibitory neurons projecting to L4 constitute specialized subcircuits distinct from the infragranular network in their connectivity and firing patterns.

Arc/Arg3.1 is robustly induced by plasticity-producing stimulation and specifically targeted to stimulated synaptic areas. To investigate the role of Arc/Arg3.1 in synaptic plasticity and learning and memory, we generated Arc/Arg3.1 knockout mice. These animals fail to form long-lasting memories for implicit and explicit learning tasks, despite intact short-term memory. Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. In addition, long-term depression is significantly impaired. Together, these results demonstrate a critical role for Arc/Arg3.1 in the consolidation of enduring synaptic plasticity and memory storage. © 2006 Elsevier Inc. All rights reserved.

Dual whole-cell voltage recordings were made from synaptically connected layer 5 (L5) pyramidal neurones in slices of the young (P14-P16) rat neocortex. The Ca2+ buffers BAPTA or EGTA were loaded into the presynaptic neurone via the pipette recording from the presynaptic neurone to examine their effect on the mean and the coefficient of variation (c.v.) of single fibre EPSP amplitudes, referred to as unitary EPSPs. The fast Ca2+ buffer BAPTA reduced unitary EPSP amplitudes in a concentration dependent way. With 0.1 mm BAPTA in the pipette, the mean EPSP amplitude was reduced by 14 ± 2.8% (mean ±s.e.m., n = 7) compared with control pipette solution, whereas with 1.5 mm BAPTA, the mean EPSP amplitude was reduced by 72 ± 1.5% (n = 5). The concentration of BAPTA that reduced mean EPSP amplitudes to one-half of control was close to 0.7 mm. Saturation of BAPTA during evoked release was tested by comparing the effect of loading the presynaptic neurone with 0.1 mm BAPTA at 2 and 1 mm[Ca2+]o. Reducing [Ca2+]o from 2 to 1 mm, thereby reducing Ca2+ influx into the terminals, decreased the mean EPSP amplitude by 60 ± 2.2% with control pipette solution and by 62 ± 1.9% after loading with 0.1 mm BAPTA (n = 7). The slow Ca2+ buffer EGTA at 1 mm reduced mean EPSP amplitudes by 15 ± 2.5% (n = 5). With 10 mm EGTA mean EPSP amplitudes were reduced by 56 ± 2.3% (n = 4). With both Ca2+ buffers, the reduction in mean EPSP amplitudes was associated with an increase in the c.v. of peak EPSP amplitudes, consistent with a reduction of the transmitter release probability as the major mechanism underlying the reduction of the EPSP amplitude. The results suggest that in nerve terminals of thick tufted L5 pyramidal cells the endogenous mobile Ca2+ buffer is equivalent to less than 0.1 mm BAPTA and that at many release sites of pyramidal cell terminals the Ca2+ channel domains overlap, a situation comparable with that at large calyx-type terminals in the brainstem. Release of transmitter in synapses is dependent on Ca2+ influx into the nerve terminals (Katz, 1969) and the binding of Ca2+ to a putative Ca2+ sensor on synaptic vesicles which in turn controls the exocytosis of a vesicle. The free cytoplasmic Ca2+ concentration ([Ca2+]i) in the vicinity of the Ca2+ sensor depends on the magnitude and time course of the Ca2+ influx into the terminal during an action potential and on the distance between the Ca2+ sensor and the site of Ca2+ entry. Fixed and mobile Ca2+ buffers affect the size and time course of the [Ca2+]i transient, depending on their concentration, association and dissociation kinetics and their mobility (Sala & Hernandez-Cruz 1990; Nowycky & Pinter, 1993; Roberts, 1994; Neher, 1995). Exogenous Ca2+ buffers, which compete for free Ca2+ with the endogenous buffers and the vesicular Ca2+ sensor, were used previously to examine the coupling between presynaptic [Ca2+]i transients and transmitter release. The lack of effect of presynaptic EGTA (80 mm), a slowly binding Ca2+ buffer, on phasic release in the squid giant synapse indicated a very fast rise of [Ca2+]i near the sensor and suggested that the distance between Ca2+ channels and the Ca2+ sensor was short (Adler et al. 1991). In contrast, at the calyx-type giant synapse of the rat medial nucleus of the trapezoid body (MNTB) relatively low concentrations of EGTA (1 mm) were sufficient to reduce phasic transmitter release (Borst & Sakmann, 1996) indicating a longer diffusional distance of Ca2+ between the Ca2+ channel and the Ca2+ sensor. In terminals of retinal bipolar neurones, EGTA and BAPTA differentially affected two phases of transmitter release which presumably represent two pools of vesicles (Mennerick & Matthews, 1996). Adding exogenous Ca2+ buffers to terminals was also used to estimate the concentration of endogenous mobile Ca2+ buffers. This yielded estimates of endogenous buffers being equivalent to 1.6 mm and 50 μm in inner ear cells and the calyx-type synapse, respectively (Roberts, 1993; Borst et al. 1995). In addition, exogenous Ca2+ buffers were used for elucidating the function of [Ca2+]i transients in short- and long-term changes in synaptic efficacy (Delaney et al. 1991; Bain & Quastel, 1992; Van der Kloot & Molgo 1993; Winslow et al. 1994; Kobayashi et al. 1995; Tank et al. 1995; Bao et al. 1997). We examined the effect of exogenous fast and slow Ca2+ buffers on evoked transmitter release in terminals of the axodendritic synaptic contacts between neighbouring pyramidal neurones in layer 5 (L5) of rat neocortex (Markram et al. 1997). Simultaneous pre- and postsynaptic whole-cell voltage recordings (WCR) from L5 pyramidal neurones were made and multiple, sequential WCRs from the same presynaptic neurone with different pipette solutions containing either the fast binding Ca2+ buffer BAPTA or the slow binding buffer EGTA or with control solution. The mean EPSP amplitudes were measured before, during and after buffer loading of the presynaptic neurone. The results show that both the slow and the fast binding buffers, at relatively low concentrations, reversibly reduced the evoked transmitter release comparable with the results obtained at the axosomatic synapse of the MNTB.

The bursting K+ channel is the most common channel in fused Torpedo presynaptic nerve terminals. It possesses the property of 'statistical memory', demonstrated by non-random probability of channel opening. We examined the voltage dependence of the statistical memory and report that removal of channel inactivation by hyperpolarization abolishes it. Addition of the potassium channel blocker 4-aminopyridine to the bath solution led to disappearance of statistical memory, while raising extracellular potassium concentration had the opposite effect. Another common channel at Torpedo nerve terminals which is a non-selective channel did not exhibit statistical memory. We conclude that statistical memory is a channel-specific phenomenon and speculate regarding its possible role in cellular and network properties of the nervous system.