Rett Syndrome (RTT) is a devastating neurological disorder that is caused by mutations in the MECP2 gene. Mecp2-mutant mice have been used as a model system to study the disease mechanism. Our previous work has suggested that MeCP2 malfunction in neurons is the primary cause of RTT in the mouse. However, the neurophysiological consequences of MeCP2 malfunction remain obscure. Using whole-cell patch-clamp recordings in cortical slices, we show that spontaneous activity of pyramidal neurons is reduced in Mecp2-mutant mice. This decrease is not caused by a change in the intrinsic properties of the recorded neurons. Instead, the balance between cortical excitation and inhibition is shifted to favor inhibition over excitation. Moreover, analysis of the miniature excitatory postsynaptic currents (mEPSCs)͞inhibitory postsynaptic currents (mIPSCs) in the Mecp2-mutant cortex reveals a reduction in mEPSC amplitudes, without significant change in the average mIPSC amplitude or frequency. These findings provide the first detailed electrophysiological analysis of Mecp2-mutant mice and provide a framework for understanding the pathophysiology of the disease and tools for studying the underlying disease mechanisms.autism ͉ cortical circuit ͉ MeCP2 ͉ mental retardation R ett Syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mental retardation, autistic behavior, and loss of previously acquired skills, including purposeful hand use and expressive language (1). Affected individuals begin to acquire motor and cognitive function normally but then regress after 6-18 months. The disease is sex-linked and is due, in most cases, to abnormal function of a single gene, the methyl CpG-binding protein MECP2 (2). Deletion of all, or the third exon, of the Mecp2 gene produces functional nulls and recapitulates, in mice, many features of the human disorder (3, 4). Mice with truncated MeCP2 also recapitulate many RTT features (5). Mecp2-null mice are normal until 5 weeks of age, when they begin to exhibit abnormal behavior resembling symptoms observed in RTT patients. Brain-specific Mecp2-mutant mice show pathological symptoms identical to those found in the germline Mecp2-null mice, thereby implicating MeCP2 malfunction in the brain as the primary cause of RTT (3). Transgenic expression of MeCP2 in postmitotic neurons in the Mecp2-mutant mice rescues the RTT phenotype (6). Overexpression of MeCP2 in postmitotic neurons in WT mice also causes behavioral and physiological abnormalities (6, 7). Taken together, these data strongly argue for the importance of MeCP2 function during the normal maturation and refinement of neural circuits, which may be compromised in Mecp2-mutant mice.Despite profound behavioral abnormalities and premature death, the neuropathological phenotype is remarkably subtle in Mecp2-mutant mice. The mutant brain weighs Ϸ20-25% less than the WT. Mutant hippocampal CA2 pyramidal neurons are Ϸ15-25% smaller than WT neurons (3). Mutant neocortical projection neurons have simplified dendritic arbors (8). Ye...

Visual deprivation during a developmental sensitive period markedly alters visual cortical response properties, but the changes in intracortical circuitry that underlie these effects are poorly understood. Here we use a slice preparation of rat primary visual cortex to show that 2 d of prior visual deprivation early in life increases the excitability of layer 4 circuitry. Slice recordings showed that spontaneous activity of layer 4 star pyramidal neurons increased 25-fold after 2 d of visual deprivation between postnatal days (P) 15 and P17. This effect was mediated by increased net excitatory and decreased net inhibitory synaptic drive. Paired recordings showed that excitatory connections between star pyramidal neurons doubled in amplitude, whereas inhibitory connections decreased or increased depending on the interneuron class. These effects reversed when vision was restored. This dynamic adjustment of the excitation-inhibition balance may allow the networks within layer 4 to maintain stable levels of activity in the face of variable sensory input.

The fine-tuning of circuits in sensory cortex requires sensory experience during an early critical period. Visual deprivation during the critical period has catastrophic effects on visual function, including loss of visual responsiveness to the deprived eye, reduced visual acuity, and loss of tuning to many stimulus characteristics. These changes occur faster than the remodelling of thalamocortical axons, but the intracortical plasticity mechanisms that underlie them are incompletely understood. Long-term depression of excitatory intracortical synapses has been proposed as a general candidate mechanism for the loss of cortical responsiveness after visual deprivation. Alternatively (or in addition), the decreased ability of the deprived eye to activate cortical neurons could be due to enhanced intracortical inhibition. Here we show that visual deprivation leaves excitatory connections in layer 4 (the primary input layer to cortex) unaffected, but markedly potentiates inhibitory feedback between fast-spiking basket cells (FS cells) and star pyramidal neurons (star pyramids). Further, a previously undescribed form of long-term potentiation of inhibition (LTPi) could be induced at synapses from FS cells to star pyramids, and was occluded by previous visual deprivation. These data suggest that potentiation of inhibition is a major cellular mechanism underlying the deprivation-induced degradation of visual function, and that this form of LTPi is important in fine-tuning cortical circuitry in response to visual experience.

Sensory experience is crucial for shaping the cortical microcircuit during development and is thought to modify network function through several forms of Hebbian and homeostatic plasticity. Where and when these different forms of plasticity are expressed at particular synapse types within cortical microcircuits, and how they interact, is poorly understood. Here we investigated how two different visual deprivation paradigms, lid suture (LS) and intraocular TTX, affect the local microcircuit within layer 2/3 of rat visual cortex during the classical critical period for visual system plasticity. Both forms of visual deprivation produced a compensatory increase in the spontaneous firing of layer 2/3 pyramidal neurons in acute slices derived from monocular visual cortex. TTX increased spontaneous activity through an increase in the excitation/inhibition (E/I) balance within layer 2/3. In contrast, LS decreased the E/I balance by strongly depressing excitatory transmission, and the homeostatic increase in spontaneous activity was instead achieved through an increase in the intrinsic excitability of layer 2/3 pyramidal neurons. The microcircuit in layer 2/3 can thus use different forms of homeostatic plasticity to compensate for the loss of visual drive, depending on the specific demands produced by visual experience. The existence of multiple, partially redundant forms of homeostatic plasticity may ensure that network compensation can be achieved in response to a wide range of sensory perturbations.

Neurons process information in a highly nonlinear manner, generating oscillations, bursting, and resonance, enhancing responsiveness at preferential frequencies. It has been proposed that slow repolarizing currents could be responsible for both oscillation/burst termination and for high-pass filtering that causes resonance (Hutcheon and Yarom, 2000). However, different mechanisms, including electrotonic effects (Mainen and Sejinowski, 1996), the expression of resurgent currents (Raman and Bean, 1997), and network feedback, may also be important. In this study we report theta-frequency (3-12 Hz) bursting and resonance in rat cerebellar granule cells and show that these neurons express a previously unidentified slow repolarizing K ϩ current (I K-slow ). Our experimental and modeling results indicate that I K-slow was necessary for both bursting and resonance. A persistent (and potentially a resurgent) Na ϩ current exerted complex amplifying actions on bursting and resonance, whereas electrotonic effects were excluded by the compact structure of the granule cell. Theta-frequency bursting and resonance in granule cells may play an important role in determining synchronization, rhythmicity, and learning in the cerebellum.

SUMMARY NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders.

Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome, an autism spectrum-associated disorder with a host of neurological and sensory symptoms, but the pathogenic mechanisms remain elusive. Neuronal circuits are shaped by experience during critical periods of heightened plasticity. The maturation of cortical GABA inhibitory circuitry, the parvalbumin + (PV + ) fast-spiking interneurons in particular, is a key component that regulates the initiation and termination of the critical period. Using MeCP2-null mice, we examined experience-dependent development of neural circuits in the primary visual cortex. The functional maturation of parvalbumin interneurons was accelerated upon vision onset, as indicated by elevated GABA synthetic enzymes, vesicular GABA transporter, perineuronal nets, and enhanced GABA transmission among PV interneurons. These changes correlated with a precocious onset and closure of critical period and deficient binocular visual function in mature animals. Reduction of GAD67 expression rescued the precocious opening of the critical period, suggesting its major role in MECP2-mediated regulation of experience-driven circuit development. Our results identify molecular changes in a defined cortical cell type and link aberrant developmental trajectory to functional deficits in a model of neuropsychiatric disorder.critical period plasticity | parvalbumin interneurons | visual cortex | Rett syndrome | MeCP2

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 GABA B -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.