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Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5-/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5-/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5-/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development. [ABSTRACT FROM AUTHOR]

In primary sensory cortices, thalamocortical (TC) inputs can directly activate excitatory and inhibitory neurons. In vivo experiments in the main input layer (L4) of primary visual cortex (V1) have shown that excitatory and inhibitory neurons have different tuning properties. The different functional properties may arise from distinct intrinsic properties of L4 neurons, but could also depend on cell type-specific properties of the synaptic inputs from the lateral geniculate nucleus of the thalamus (LGN) onto L4 neurons. While anatomical studies identified LGN inputs onto both excitatory and inhibitory neurons in V1, their synaptic properties have not been investigated. Here we used an optogenetic approach to selectively activate LGN terminal fields in acute coronal slices containing V1, and recorded monosynaptic currents from excitatory and inhibitory neurons in L4. LGN afferents made monosynaptic connections with pyramidal (Pyr) and fast-spiking (FS) neurons. TC EPSCs on FS neurons were larger and showed steeper short-term depression in response to repetitive stimulation than those on Pyr neurons. LGN inputs onto Pyr and FS neurons also differed in postsynaptic receptor composition and organization of presynaptic release sites. Together, our results demonstrate that LGN input onto L4 neurons in mouse V1 have target-specific presynaptic and postsynaptic properties. Distinct mechanisms of activation of feedforward excitatory and inhibitory neurons in the main input layer of V1 are likely to endow neurons with different response properties to incoming visual stimuli. [ABSTRACT FROM AUTHOR]

The mammalian neocortex is composed of a variety of cell types organized in a highly interconnected circuit. GABAergic neurons account for only about 20% of cortical neurons. However, they show widespread connectivity and a high degree of diversity in morphology, location, electrophysiological properties and gene expression. In addition, distinct populations of inhibitory neurons have different sensory response properties, capacities for plasticity and sensitivities to changes in sensory experience. In this review we summarize experimental evidence regarding the properties of GABAergic neurons in primary sensory cortex. We will discuss how distinct GABAergic neurons and different forms of GABAergic inhibitory plasticity may contribute to shaping sensory cortical circuit activity and function. [ABSTRACT FROM AUTHOR]

The broad connectivity of inhibitory interneurons and the capacity of inhibitory synapses to be plastic make them ideal regulators of the level of excitability of many neurons simultaneously. Whether inhibitory synaptic plasticity may also contribute to the selective regulation of single neurons and local microcircuits activity has not been investigated. Here we demonstrate that in rat primary visual cortex inhibitory synaptic plasticity is connection specific and depends on the activation of postsynaptic GABAB-Gi/o protein signaling. Through the activation of this intracellular signaling pathway, inhibitory plasticity can alter the state of a single postsynaptic neuron and directly affect the induction of plasticity at its glutamatergic inputs. This interaction is modulated by sensory experience. Our data demonstrate that in recurrent circuits, excitatory and inhibitory forms of synaptic plasticity are not integrated as independent events, but interact to cooperatively drive the activity-dependent rewiring of local microcircuits. [ABSTRACT FROM AUTHOR]

Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer-specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer-specific synaptic organization and plasticity. [ABSTRACT FROM AUTHOR]

Neural circuits are extensively refined by sensory experience during postnatal development. How the maturation of recurrent cortical synapses may contribute to events regulating the postnatal refinement of neocortical microcircuits remains controversial. Here we show that, in the main input layer of rat primary visual cortex, layer 4 (L4), recurrent excitatory synapses are endowed with multiple, devel-opmentally regulated mechanisms for induction and expression of excitatory synaptic plasticity. Maturation of L4 synapses and visual experience lead to a sharp switch in sign and mechanisms for plasticity at recurrent excitatory synapses in L4 at the onset of the critical period for visual cortical plasticity. The state of maturation of excitatory pyramidal neurons allows neurons to engage different mechanisms for plasticity in response to the same induction paradigm. Experience is determinant for the maturation of L4 synapses, as well as for the transition between forms of plasticity and the mechanisms they may engage. These results indicate a tight correlation between the effects of sensory drive and maturation on cortical neurons and provide a new set of cellular mechanisms engaged in the postnatal refinement of cortical circuits. [ABSTRACT FROM AUTHOR]

AMPA-receptor trafficking plays a central role in excitatory plasticity, especially during development. Changes in the number of AMPA receptors and time spent at the synaptic surface are important factors of plasticity that directly affect long-term potentiation (LTP), long-term depression (LTD), synaptic scaling, and the excitatory-inhibitory (E/I) balance in the developing cortex. Experience-dependent changes in synaptic strength in visual cortex (V1) use a molecularly distinct AMPA trafficking pathway that includes the GluA2 subunit. We studied developmental changes in AMPA receptor trafficking proteins by quantifying expression of GluA2, pGluA2 (GluA2serine880), GRIP1, and PICK1 in rat visual and frontal cortex. We used Western Blot analysis of synaptoneurosome preparations of rat visual and frontal cortex from animals ranging in age from P0 to P105. GluA2 and pGluA2 followed different developmental trajectories in visual and frontal cortex, with a brief period of over expression in frontal cortex. The over expression of GluA2 and pGluA2 in immature frontal cortex raises the possibility that there may be a period of GluA2-dependent vulnerability in frontal cortex that is not found in V1. In contrast, GRIP1 and PICK1 had the same developmental trajectories and were expressed very early in development of both cortical areas. This suggests that the AMPA-interacting proteins are available to begin trafficking receptors as soon as GluA2-containing receptors are expressed. Finally, we used all four proteins to analyze the surface-to-internalization balance and found that this balance was roughly equal across both cortical regions, and throughout development. Our finding of an exquisite surface-to-internalization balance highlights that these AMPA receptor trafficking proteins function as a tightly controlled system in the developing cortex. [ABSTRACT FROM AUTHOR]

Postnatal cortical circuit development is characterized by windows of heightened plasticity that contribute to the acquisition of mature connectivity and function. What drives the transition between different critical plasticity windows is not known. Here we show that a switch in sign of inhibitory plasticity correlates with the reported transition between the precritical period (pre-CP) and the critical period (CP) for ocular dominance plasticity (ODP). In layer 4 of binocular visual cortex (V1b), depression of inhibitory synapses onto pyramidal neurons is induced when rats are monocularly deprived for 2 d at the end of the third postnatal week (pre-CP), whereas potentiation is induced if the monocular deprivation is started in the fourth postnatal week (CP). The magnitude of potentiation increases with deprivations started close to the peak of the CP for ODP. The direction of inhibitory plasticity depends on the differential manipulation of circuits activated by the two eyes. During development, these two forms of plasticity shift the balance between excitation and inhibition of the circuit in opposite directions, whereas the excitatory synaptic drive remains unaffected. Inhibitory plasticity is thus fundamental in modulating cortical circuit refinement and might be one of the mechanisms promoting ocular dominance shifts. [ABSTRACT FROM AUTHOR]

Thalamocortical circuits are central to sensory and cognitive processing. Recent work suggests that the thalamocortical inputs onto L4 and L6, the main input layers of neocortex, are activated differently by visual stimulation. Whether these differences depend on layer-specific organization of thalamocortical circuits; or on specific properties of synapses onto receiving neurons is unknown. Here we combined optogenetic stimulation of afferents from the visual thalamus and paired recording electrophysiology in L4 and L6 of rat primary visual cortex to determine the organization and plasticity of thalamocortical synapses. We show that thalamocortical inputs onto L4 and L6 differ in synaptic dynamics and sensitivity to visual drive. We also demonstrate that the two layers differ in the organization of thalamocortical and recurrent intracortical connectivity. In L4, a significantly larger proportion of excitatory neurons responded to light activation of thalamocortical terminal fields than in L6. The local microcircuit in L4 showed a higher degree of recurrent connectivity between excitatory neurons than the microcircuit in L6. In addition, L4 recurrently connected neurons were driven by thalamocortical inputs of similar magnitude indicating the presence of local subnetworks that may be activated by the same axonal projection. Finally, brief manipulation of visual drive reduced the amplitude of light-evoked thalamocortical synaptic currents selectively onto L4. These data are the first direct indication that thalamocortical circuits onto L4 and L6 support different aspects of cortical function through layer-specific synaptic organization and plasticity.

Neural circuits are extensively refined by sensory experience during postnatal development. How the maturation of recurrent cortical synapses may contribute to events regulating the postnatal refinement of neocortical microcircuits remains controversial. Here we show that, in the main input layer of rat primary visual cortex, layer 4 (L4), recurrent excitatory synapses are endowed with multiple, developmentally regulated mechanisms for induction and expression of excitatory synaptic plasticity. Maturation of L4 synapses and visual experience lead to a sharp switch in sign and mechanisms for plasticity at recurrent excitatory synapses in L4 at the onset of the critical period for visual cortical plasticity. The state of maturation of excitatory pyramidal neurons allows neurons to engage different mechanisms for plasticity in response to the same induction paradigm. Experience is determinant for the maturation of L4 synapses, as well as for the transition between forms of plasticity and the mechanisms they may engage. These results indicate a tight correlation between the effects of sensory drive and maturation on cortical neurons and provide a new set of cellular mechanisms engaged in the postnatal refinement of cortical circuits.

Proper wiring of neural circuits during development depends on both molecular cues that guide connectivity and activity-dependent mechanisms that use patterned activation to adjust the strength and number of synaptic connections. In this chapter, we discuss some of the plasticity mechanisms underlying the experience-dependent rewiring of visual cortical microcircuits focusing on layer 4 of rat primary visual cortex. The microcircuit in layer 4 has the ability to regulate its excitability by shifting the balance between excitatory and inhibitory synaptic transmission in an experience-dependent manner. Early in postnatal development (shortly after eye opening), visual deprivation activates several forms of homeostatic plasticity that cooperate to adjust layer 4 excitability to compensate for reduced sensory drive. In contrast, during the classical sensitive period for rodent visual system plasticity, this homeostatic response is replaced by mechanisms that reduce the responsiveness of deprived cortex. We discuss this developmentally regulated switch in plasticity within layer 4 and how this might depend on the maturation of excitatory and inhibitory monosynaptic connections. Based on our published data, we propose inhibitory plasticity as an important player in circuit refinement that can contribute both to the compensatory forms of circuit plasticity in the early stages of development and to the pathological loss of function induced by visual deprivation during the critical period.

In the last decade, the physiology of cerebellar neurons and synapses has been extended to a considerable extent. We have found that the mossy fiber-granule cell relay can generate a complex form of long-term potentiation (mf-GrC LTP) following high-frequency mf discharge. Induction. Mf-GrC LTP depends on NMDA and mGlu receptor activation, intracellular Ca(2+) increase, PKC activation, and NO production. The preventative action of intracellular agents (BAPTA, PKC-inhibitors) and of membrane hyperpolarization, and the correlated increase in intracellular Ca(2+) observed using fluorescent dyes, indicate that induction occurs postsynaptically. Expression. Expression includes three components: (a) an increase of synaptic currents, (b) an increase of intrinsic excitability in GrC, and (c) an increase of intrinsic excitability in mf terminals. Based on quantal analysis, the EPSC increase is mostly explained by enhanced neurotransmitter release. NO is a candidate retrograde neurotransmitter which could determine both presynaptic current changes and LTP. NO cascade blockers inhibit both presynaptic current changes and LTP. The increase in intrinsic excitability involves a raise in apparent input resistance in the subthreshold region and a spike threshold reduction. Together with other forms of cerebellar plasticity, mf-GrC LTP opens new hypothesis on how the cerebellum processes incoming information.