SUMMARY Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ~30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6+/− mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6+/− mice. These pro-cognitive effects were frequency-specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven gamma oscillations in cognitive domains at the core of schizophrenia.

Light deprivation lowers the threshold for long-term depression (LTD) and long-term potentiation (LTP) in visual cortex by a process termed metaplasticity, but the mechanism is unknown. The decreased LTD/P threshold correlates with a decrease in the ratio of NR2A to NR2B subunits of cortical NMDA receptors (NMDARs) and a slowing of NMDAR-mediated excitatory postsynaptic currents (EPSCs). However, whether and how changes in NR2 subunit expression contribute to LTD and LTP have been controversial. In the present study, we used an NR2A knockout (KO) mouse to examine the role of this subunit in the experience-dependent modulation of NMDAR properties, LTD, and LTP. We found that deletion of NR2A abrogates the effects of visual experience on NMDAR EPSCs and prevents metaplasticity of LTP and LTD. These data support the hypothesis that experience-dependent changes in NR2A/B are functionally significant and yield a mechanism for an adjustable synaptic modification threshold in visual cortex.

Summary Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST+ interneurons, that increases the ratio of PV/SST interneurons, ectopic PV+ projections in layer I, and increases in inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in EEG power. Using MGE transplantation, we test for cell-autonomous functional differences between human PTEN wild type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio compared to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable to functionally test ASD alleles in vivo.

Bidirectional synaptic plasticity during development ensures that appropriate synapses in the brain are strengthened and maintained while inappropriate connections are weakened and eliminated. This plasticity is well illustrated in mouse visual cortex, where monocular deprivation during early postnatal development leads to a rapid depression of inputs from the deprived eye and a delayed strengthening of inputs from the non-deprived eye. The mechanisms that control these bidirectional synaptic modifications remain controversial. Here we demonstrate, both in vitro and in vivo, that genetic deletion or reduction of the NR2A NMDA receptor subunit impairs activity-dependent weakening of synapses and enhances the strengthening of synapses. Although brief monocular deprivation in juvenile WT mice normally causes a profound depression of the deprived-eye response without a change in the non-deprived eye response, NR2A-knockout mice fail to exhibit deprivation-induced depression and instead exhibit precocious potentiation of the non-deprived eye inputs. These data support the hypothesis that a reduction in the NR2A/B ratio during monocular deprivation is permissive for the compensatory potentiation of non-deprived inputs.metaplasticity ͉ synaptic homeostasis ͉ synaptic scaling ͉ visual evoked potential ͉ BCM theory T he circuitry of primary visual cortex is susceptible to changes in sensory experience during early postnatal development, as evidenced by the well studied paradigm of monocular deprivation (MD) (1). MD and reverse occlusion studies demonstrate that the strength of synapses is bidirectionally modifiable (2-4). A detailed time course of the synaptic events following MD in mice shows that the initial consequence is a rapid depression of the deprived-eye inputs followed by a delayed strengthening of the non-deprived eye inputs (5). However, little is known about the molecular mechanisms that regulate the susceptibility of synapses to bidirectional modifications in their strength.Bidirectional synaptic plasticity has been studied in slice recordings of visual cortex in the form of long-term potentiation (LTP) and long-term depression (LTD), whereby synapses strengthen and weaken in response to stimulation (6). These activity-dependent modifications can be modeled by a learning rule whereby high levels of post-synaptic activation (evoked electrically by high-frequency stimulation) induce LTP and smaller levels of post-synaptic activation (evoked electrically by lower-frequency stimulation) induce LTD (7). The crossover point from synaptic weakening to strengthening is called the modification threshold ( m ). An important feature of this model is that the value of m is not fixed; rather, its value can ''slide'' as a function of the history of post-synaptic activation. According to the BCM theory, closing the dominant contralateral eye first leads to depression of the deprived synapses, followed by a leftward shift in m caused by the reduction in average cortical activity. This shift in m is permissive for the subse...