Lack of a sensory input not only alters the cortical circuitry subserving the deprived sense, but also produces compensatory changes in the functionality of other sensory modalities. Here we report that visual deprivation produces opposite changes in synaptic function in primary visual and somatosensory cortices in rats, which are rapidly reversed by visual experience. This type of bidirectional cross-modal plasticity is associated with changes in synaptic AMPA receptor subunit composition.Loss of vision is usually accompanied by the increased functionality of other sensory modalities 1,2 . Systems-level analyses of cross-modal plasticity have revealed anatomical and functional rewiring of cortical circuits 3 . However, little is known about the cellular and molecular mechanisms underlying this type of plasticity. Here we examined whether manipulation of visual experience can induce bidirectional cross-modal plasticity of synaptic function in primary sensory cortices, and investigated the molecular mechanisms underlying this form of plasticity.To study cross-modal changes in synaptic function by visual deprivation, we dark-reared 4-week-old Long-Evans rats for a period of 1 week and then measured AMPA receptor (AMPAR)-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer 2/3 pyramidal neurons in slices from primary visual, somatosensory and auditory cortex (Supplementary Methods online). In visual cortex, dark rearing produced an increase in mESPC amplitude that was reversed by re-exposing the rats to lighted conditions for 2 d Correspondence should be addressed to H.-K.L. (hlee21@umd.edu). 4 Current address: Brain Science Institute, Riken, Wako City, Saitama, Japan. 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. AUTHOR CONTRIBUTIONSA.G. and B.J. conducted the electrophysiology experiments (mEPSC recordings and rectification measurements, respectively) and assisted in writing the manuscript; L.W.X. and L.S. performed the biochemistry experiments; A.K. oversaw the electrophysiology (rectification measurements), contributed to discussions on experimental designs and collaborated on manuscript writing; H.-K.L. designed the studies, oversaw experiments, contributed to the electrophysiology (mEPSC recordings) and biochemistry and wrote the manuscript. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. (normal-reared (NR): 10.7 ± 0.6 pA, n = 8; dark-reared (DR): 12.4 ± 0.4 pA, n = 16; re-exposure to light (L): 10.7 ± 0.4 pA, n = 13; analysis of variance (ANOVA): F 2,34 = 5.968, P < 0.01; Fig. 1a). Notably, we observed the opposite changes in somatosensory cortex, where 1 week of dark rearing decreased the amplitude of mEPSCs and 2 d of light exposure reversed this effect (NR: 13.8 ± 0.8 pA, n = 12; DR: 11.3 ± 0.7 pA, n = 16; L: 14.1 ± 0.9 pA, n = 16; ANOVA: F 2,40 = 3.830, P < 0.04; Fig. 1b). Changes in synaptic transmission by dark rearing seems to be general for pr...

SUMMARY Endocannabinoids are widely regarded as negative modulators of presynaptic release. Here we present evidence that in visual cortex endocannabinoids are crucial for the maturation of GABAergic release. We found that between eye opening and puberty, release changes from an immature state with high release probability, short-term depression (STD) and high release variability during irregular patterned activity, to a mature state with reduced release probability, STD and variability. This transition requires visual experience and stimulation of CB1 cannabinoid receptors as it is mimicked by administration of CB1 agonists, blocked by antagonists and is absent in CB1R KO mice. In immature slices, activation of CB1 receptors induces long-term depression of inhibitory responses (iLTD), and a reduction in STD and response variability. Based on these findings, we propose that visually induced endocannabinoid-dependent iLTD mediates the developmental decrease in release probability, STD and response variability, which are characteristic of maturation of cortical GABAergic inhibition.

. Our analysis revealed that LTP and LTD in layer IV principal cells is lost shortly after the eyes open, but persists in layers II/III beyond puberty. These results suggest that plasticity proceeds sequentially through cortical layers in a manner that parallels the flow of information during sensory processing.

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Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of ␣1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP 3 ). LTD was also impaired by intracellular application of PLC or IP 3 receptor blockers, and it was absent in mice lacking PLC␤1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.

Genetic manipulation for "knockout" (KO) is a useful tool for characterizing a target gene. However, its shortcomings that need to be overcome hinder its easy and ready usage in ordinary laboratories. Here we describe a knockdown technique termed the RNA interference (RNAi)-induced gene silencing by local electroporation (RISLE). Small interfering RNA (siRNA) introduction by electroporation into a specific brain region results in a marked reduction in the expression levels of both the mRNA and protein of the target genes such as GluR2 and Cox-1 without affecting the expression levels of proteins other than that of the target protein or causing pathological changes in the target tissues. The effective electrical pulses are relatively weak, consisting of a strong short pulse and a weak long pulse applied in tandem. RISLE can knock down a gene at the target region, for example, the visual cortex and the CA1 region of the hippocampus, without affecting other regions. Moreover, the knockdown models constructed using this technique have physiological functions consistent with previous findings, that is, glutamate release from presynaptic sites, long-term potentiation (LTP), and long-term depression (LTD). These results suggest that this technique is applicable and characterized by spatial flexibility, temporal accessibility, and ease of establishment of knockdown models. The intactness of the tissue subjected to RISLE is due to the weak electrical pulses applied and the limited area of gene silencing. Thus RISLE may be applicable to disease therapy in the future.

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.

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