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• W2178727006 abstract "•Mecp2 loss in PV+ and SOM+ neurons leads to non-overlapping neurological phenotypes•Mecp2 deletion in PV+ neurons causes motor, sensory, memory, and social deficits•Mecp2 deletion in SOM+ neurons causes seizures and stereotypies Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. Rett syndrome (RTT) is a devastating postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) (Amir et al., 1999Amir R.E. Van den Veyver I.B. Wan M. Tran C.Q. Francke U. Zoghbi H.Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.Nat. Genet. 1999; 23: 185-188Crossref PubMed Scopus (3795) Google Scholar). Affected children appear to develop normally during the first year of life but quickly regress, losing language and acquired motor skills and developing ataxia, respiratory dysrhythmias, seizures, cognitive deficits, and stereotyped hand movements (Chahrour and Zoghbi, 2007Chahrour M. Zoghbi H.Y. The story of Rett syndrome: from clinic to neurobiology.Neuron. 2007; 56: 422-437Abstract Full Text Full Text PDF PubMed Scopus (927) Google Scholar). Because the RTT phenotype is so broad, several conditional knockout mice have been generated to dissect the contribution of various brain regions and neuronal subtypes to the pathogenesis of the disorder. For instance, mice with Mecp2 conditionally deleted from the medulla and spinal cord reproduce the respiratory dysrhythmias and premature death (Ward et al., 2011Ward C.S. Arvide E.M. Huang T.W. Yoo J. Noebels J.L. Neul J.L. MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan.J. Neurosci. 2011; 31: 10359-10370Crossref PubMed Scopus (64) Google Scholar), while a forebrain excitatory neuron deletion mouse develops seizures (Zhang et al., 2014Zhang W. Peterson M. Beyer B. Frankel W.N. Zhang Z.W. Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures.J. Neurosci. 2014; 34: 2754-2763Crossref PubMed Scopus (85) Google Scholar). Unexpectedly, depleting MeCP2 in inhibitory neurons using a Viaat-Cre allele that targets GABAergic neurons recapitulates almost the entire spectrum of RTT features, including motor, sensory, memory, social, and autonomic dysfunction as well as stereotyped behaviors (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar). These results underscore the importance of MeCP2 for the function of inhibitory neurons and the breadth of neurological consequences that follow moderate compromise of inhibitory signaling. The various interneuron subtypes, which exhibit a striking range of morphological, electrophysiological, and molecular properties, seem to possess distinct circuit functions (Kepecs and Fishell, 2014Kepecs A. Fishell G. Interneuron cell types are fit to function.Nature. 2014; 505: 318-326Crossref PubMed Scopus (641) Google Scholar, Klausberger and Somogyi, 2008Klausberger T. Somogyi P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.Science. 2008; 321: 53-57Crossref PubMed Scopus (1427) Google Scholar) and appear to be recruited by different behavioral events (Kvitsiani et al., 2013Kvitsiani D. Ranade S. Hangya B. Taniguchi H. Huang J.Z. Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.Nature. 2013; 498: 363-366Crossref PubMed Scopus (292) Google Scholar, Wolff et al., 2014Wolff S.B. Gründemann J. Tovote P. Krabbe S. Jacobson G.A. Müller C. Herry C. Ehrlich I. Friedrich R.W. Letzkus J.J. Lüthi A. Amygdala interneuron subtypes control fear learning through disinhibition.Nature. 2014; 509: 453-458Crossref PubMed Scopus (317) Google Scholar). For instance, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons, which each constitute 30%–40% of the entire inhibitory neuronal population in the cortex (Rudy et al., 2011Rudy B. Fishell G. Lee S. Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.Dev. Neurobiol. 2011; 71: 45-61Crossref PubMed Scopus (837) Google Scholar), have been implicated in different stages of foraging behavior, regulated by the anterior cingulate cortex, and have different functions in the amygdala during cued memory (Kvitsiani et al., 2013Kvitsiani D. Ranade S. Hangya B. Taniguchi H. Huang J.Z. Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.Nature. 2013; 498: 363-366Crossref PubMed Scopus (292) Google Scholar, Wolff et al., 2014Wolff S.B. Gründemann J. Tovote P. Krabbe S. Jacobson G.A. Müller C. Herry C. Ehrlich I. Friedrich R.W. Letzkus J.J. Lüthi A. Amygdala interneuron subtypes control fear learning through disinhibition.Nature. 2014; 509: 453-458Crossref PubMed Scopus (317) Google Scholar). To better understand how these two subpopulations individually contribute to complex behaviors in vivo, it would be ideal to partially disable their function rather than ablate them, so as to avoid the confound of widespread cell death or complete collapse of the neural circuit. Because loss of MeCP2 creates just such a partial dysfunction of the affected neuron, we conditionally deleted Mecp2 from PV+ neurons and from SOM+ neurons to explore the behavioral consequences. While neither conditional knockout mouse developed the full array of constitutive Mecp2-deletion features, the two lines together recapitulated many of the Rett-like phenotypes: the PV conditional knockouts developed motor, sensory, social, and cognitive deficits, while the SOM conditional knockout mice exhibited repetitive behaviors and seizures. These two models reinforce the importance of a robust functionality of these neurons for normal behavior. To confirm that MeCP2 is expressed in PV+ and SOM+ neurons, we stained brain sections from adult SOM-Cre: Ai9 mice, which express a tdTomato reporter in SOM+ neurons, with antibodies for MeCP2 and PV. Both PV+ and SOM+ neurons expressed MeCP2 in various brain regions (Figure 1A). MeCP2 signal was comparable between PV+ and SOM+ neurons in the CA1 region of the hippocampus (n = 5 mice, p = 0.96, paired t test) and in the striatum (n = 5 mice, p = 0.19, paired t test), while the signal was somewhat stronger in SOM+ neurons in the cortex (layer 2/3, n = 5 mice, p = 0.013, paired t test) (Figure 1B). We also confirmed that there was little overlap between PV+ and SOM+ cells, which was consistent with previous reports (Rudy et al., 2011Rudy B. Fishell G. Lee S. Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.Dev. Neurobiol. 2011; 71: 45-61Crossref PubMed Scopus (837) Google Scholar); cells expressing both PV and SOM accounted for 3.7% ± 2.8% of neurons in the cortex (layer 2/3) and 5.7% ± 2.8% in the hippocampus (CA1) (n = 5 mice); however, these values may be overestimated, as the SOM-Cre:Ai9 line labels SOM+ cells throughout development. To determine the contributions of PV+ and SOM+ neurons to the behavioral features observed in Viaat-Mecp2-/y mice (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar), we generated two lines of conditional knockout mice lacking MeCP2 in either PV+ neurons (PV-Mecp2-/y) or SOM+ neurons (SOM-Mecp2-/y) by crossing Mecp2flox/+ mice (Flox) (Guy et al., 2001Guy J. Hendrich B. Holmes M. Martin J.E. Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.Nat. Genet. 2001; 27: 322-326Crossref PubMed Scopus (1216) Google Scholar) to PV-Cre (Madisen et al., 2010Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. et al.A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.Nat. Neurosci. 2010; 13: 133-140Crossref PubMed Scopus (3846) Google Scholar) and SOM-Cre (Taniguchi et al., 2011Taniguchi H. He M. Wu P. Kim S. Paik R. Sugino K. Kvitsiani D. Fu Y. Lu J. Lin Y. et al.A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.Neuron. 2011; 71: 995-1013Abstract Full Text Full Text PDF PubMed Scopus (1140) Google Scholar) mice, respectively. PV-Mecp2-/y and SOM-Mecp2-/y mice initially appeared similar to littermate control mice. Immunofluorescence staining confirmed MeCP2 expression was effectively depleted in PV+ and SOM+ cells, respectively (Figures 1C–1E). The expression of MeCP2 in SOM+ cells of PV-Mecp2-/y brains and in PV+ cells of SOM-Mecp2-/y mice was unaltered, indicating no compensation of Mecp2 expression in the unmanipulated inhibitory neuron subtypes (Figure S1). We next characterized PV-Mecp2-/y and SOM-Mecp2-/y mice using multiple behavioral assays. Because the Mecp2flox/y conditional allele causes a constitutive 50% reduction of MeCP2 levels (Samaco et al., 2008Samaco R.C. Fryer J.D. Ren J. Fyffe S. Chao H.T. Sun Y. Greer J.J. Zoghbi H.Y. Neul J.L. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome.Hum. Mol. Genet. 2008; 17: 1718-1727Crossref PubMed Scopus (159) Google Scholar), we expected the Flox mice to differ slightly from wild-type as the animals age; we therefore analyzed all data by comparing conditional knockout mice with male littermates of three control groups: wild-type (WT), PV-Cre alone or SOM-Cre alone, and Mecp2flox/y alone (Flox). Interestingly, PV-Mecp2-/y and SOM-Mecp2-/y mice developed completely different neurological deficits. PV-Mecp2-/y mice developed progressive ataxia, as shown by reduced latency to fall in both the rotarod (Figures 2A and 2B ) and dowel walk assays (Figure 2C). The ataxia was apparent at 6 weeks and worsened by 20 weeks (Figures 2A and 2B). Consistent with this observation, PV-Mecp2-/y mice developed widely splayed hind limbs after 10 weeks (Figures S2A and S2B) and hind limb retraction after 15 weeks of age (Figure 2D); they also showed impaired performance on the marble-burying test, suggesting forelimb incoordination (Figure S2C). The SOM-Mecp2-/y mice displayed none of these motor deficits (Figures 2E–2H and Figure S2D). PV-Mecp2-/y mice also exhibited sensory, memory, and cognitive impairments that were not apparent in SOM-Mecp2-/y mice (Figure 3). PV-Mecp2-/y mice had a significantly diminished acoustic startle response (Figure 3A) and spent significantly more time interacting with novel partner mice in a social behavior assay (Figure 3B). In addition, PV-Mecp2-/y mice developed progressive cued memory deficits (Figures 3C and 3D). The difference in freezing response to a conditioned tone between PV-Mecp2-/y and each of the three control groups became statistically significant at 15 weeks of age (Figures 3C and 3D). In contrast, SOM-Mecp2-/y mice did not show alterations in acoustic startle response, partition, or cued memory tests (Figures 3E–3H). The PV-Mecp2-/y mice thus reproduced many of the features observed in the Mecp2 null and Viaat-Mecp2-/y male mice (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar), but they did not reproduce the stereotyped behaviors (Figure 4A) or seizures. These two features were prominent, however, in the SOM-Mecp2-/y mice (Figures 4B and 4C). Like the Viaat-Mecp2-/y mice, SOM-Mecp2-/y mice showed repetitive nose-poking behavior in the hole board test (Figure 4B) (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar). Fifty percent of SOM-Mecp2-/y mice developed spontaneous epileptic seizures starting at 12 weeks (Figure 4C), with generalized tonic clonic seizures observed during routine handling (Movie S1). There was only one RTT-related feature that the PV-Mecp2-/y and SOM-Mecp2-/y mice shared: both conditional knockout lines died prematurely, with 50% mortality by 29–35 weeks of age (Figures 4D and 4E). The above behavioral studies reveal that PV-Mecp2-/y and SOM-Mecp2-/y mice develop complementary aspects of the RTT phenotype, together recapitulating the majority of the Viaat-Mecp2-/y mouse phenotype (Table 1). Neither the PV-Mecp2-/y nor the SOM-Mecp2-/y mice developed any deficits that were not observed in Viaat-Mecp2-/y mice, such as anxiety behaviors as measured in the light/dark and elevated plus maze tests (Figures S3A–S3D). It is worth noting, however, that these two lines failed to develop three features exhibited by the Viaat-Mecp2-/y mice (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar): increased pre-pulse inhibition, reduced locomotor activity, or increased body weight (Figures S3E–S3J). We also found that long-term potentiation (LTP) in the CA1 region of hippocampus was not altered in either conditional knockout (data not shown). It thus seems likely that some features of Viaat-Mecp2-/y mice are mediated by another inhibitory neuron subtype (such as glycinergic neurons, which also express the Viaat transporter) or that synergistic impairment of multiple inhibitory neurons is necessary for some RTT symptoms to appear.Table 1Phenotypic Consequences of Depleting MeCP2 in Inhibitory NeuronsFeatureViaat-Mecp2-/yPV-Mecp2-/ySOM-Mecp2-/yMedian Survival26 weeks30 weeks35 weeksMotor Incoordination↓↓−Spasticity++−Altered Startle Response↓↓−Learning and Memory Deficit↓↓−Altered Social Interaction↑↑−Stereotypy↑−↑Seizures+−+Activity Changes↓−−Sensorimotor Gating Defect↑−−Obesity+−−PV-Mecp2-y and SOM-Mecp2-y showed specific subsets of neurological features observed in Viaat-Mecp2-y mice. See also Figures S2 and S3. Open table in a new tab PV-Mecp2-y and SOM-Mecp2-y showed specific subsets of neurological features observed in Viaat-Mecp2-y mice. See also Figures S2 and S3. Loss-of-function mutations in MECP2 cause a broad array of neuropsychiatric symptoms, indicating that MeCP2 is critical for normal brain function and behavior (Chahrour and Zoghbi, 2007Chahrour M. Zoghbi H.Y. The story of Rett syndrome: from clinic to neurobiology.Neuron. 2007; 56: 422-437Abstract Full Text Full Text PDF PubMed Scopus (927) Google Scholar, Chao and Zoghbi, 2012Chao H.T. Zoghbi H.Y. MeCP2: only 100% will do.Nat. Neurosci. 2012; 15: 176-177Crossref PubMed Scopus (49) Google Scholar). The Mecp2-heterozygous female mouse reproduces many features of the human disease, such as ataxia, breathing abnormalities, abnormal sensory function, learning and memory deficits, and abnormalities in social behavior (Samaco et al., 2013Samaco R.C. McGraw C.M. Ward C.S. Sun Y. Neul J.L. Zoghbi H.Y. Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies.Hum. Mol. Genet. 2013; 22: 96-109Crossref PubMed Scopus (121) Google Scholar); the Mecp2 null male mouse develops an accelerated and more severe version of the disorder (Baker et al., 2013Baker S.A. Chen L. Wilkins A.D. Yu P. Lichtarge O. Zoghbi H.Y. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.Cell. 2013; 152: 984-996Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, Chen et al., 2001Chen R.Z. Akbarian S. Tudor M. Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.Nat. Genet. 2001; 27: 327-331Crossref PubMed Scopus (1032) Google Scholar, Guy et al., 2001Guy J. Hendrich B. Holmes M. Martin J.E. Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.Nat. Genet. 2001; 27: 322-326Crossref PubMed Scopus (1216) Google Scholar, Heckman et al., 2014Heckman L.D. Chahrour M.H. Zoghbi H.Y. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice.eLife. 2014; 3: 3Crossref Scopus (6) Google Scholar). Strikingly, most of these RTT-like features can be replicated by eliminating MeCP2 from GABAergic neurons (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar), which make up approximately 20% of the neurons in the brain. The heterogeneity of this cellular population led us to investigate the contributions of the different subtypes of inhibitory neurons to the pathogenesis of RTT. Here, we show that the two largest subtypes of GABAergic neurons, PV+ and SOM+ neurons, each contribute distinct features to the phenotype of the Viaat-Mecp2-/y mice (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar) and thus to the major features of RTT (Table 1). It is possible that some subtle phenotypic abnormalities are present in both conditional knockout models but were obscured due to comparison with the Flox mice, which express ∼50% less MeCP2 and show some behavioral changes when compared to wild-type mice, especially as they age. However, even when taking this into consideration, the contrasting features of the PV- and SOM- Mecp2-/y were clear and confirmed using multiple behavioral tests, suggesting that these two neuronal subtypes play distinct roles in the pathogenesis of RTT. Disruptions in inhibitory neuron function have been postulated to contribute to several neurodevelopmental disorders, including autism and schizophrenia (Le Magueresse and Monyer, 2013Le Magueresse C. Monyer H. GABAergic interneurons shape the functional maturation of the cortex.Neuron. 2013; 77: 388-405Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, Penzes et al., 2013Penzes P. Buonanno A. Passafaro M. Sala C. Sweet R.A. Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders.J. Neurochem. 2013; 126: 165-182Crossref PubMed Scopus (92) Google Scholar); our studies suggest that dysfunction of specific inhibitory neuron subtypes probably underlies specific symptoms in these disorders. Recent work using optogenetics has revealed that PV+ and SOM+ cells in a local circuit are activated differently during foraging behavior and acquisition of fear conditioning (Kvitsiani et al., 2013Kvitsiani D. Ranade S. Hangya B. Taniguchi H. Huang J.Z. Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.Nature. 2013; 498: 363-366Crossref PubMed Scopus (292) Google Scholar, Wolff et al., 2014Wolff S.B. Gründemann J. Tovote P. Krabbe S. Jacobson G.A. Müller C. Herry C. Ehrlich I. Friedrich R.W. Letzkus J.J. Lüthi A. Amygdala interneuron subtypes control fear learning through disinhibition.Nature. 2014; 509: 453-458Crossref PubMed Scopus (317) Google Scholar). Our findings using partial impairment of these neurons suggest additional functional roles, with PV+ neurons critical for motor and higher cognitive functions and SOM+ neurons contributing to seizure susceptibility and stereotypic behaviors. Given that most neuropsychiatric disorders do not involve total loss of a neuronal subtype and/or its function but rather are due to subtle impairment of one or more neuronal subtypes, our study sheds light on the neuroanatomical bases of some human neuropsychiatric phenotypes. Neuropsychiatric disorders that share symptoms with RTT might well involve dysfunction of PV+ and/or SOM+ neurons. PV+ and SOM+ inhibitory neurons are both widely distributed throughout the brain but differ in their firing patterns and innervation targets: PV+ neurons tend to be fast spiking and synapse onto the soma and axon initial segment of their target neurons, while SOM+ neurons spike more slowly and target dendrites (Kepecs and Fishell, 2014Kepecs A. Fishell G. Interneuron cell types are fit to function.Nature. 2014; 505: 318-326Crossref PubMed Scopus (641) Google Scholar). Because MeCP2 is expressed in both neuronal subtypes and throughout the brain (Figures 1A and 1B), the distinct behavioral features of PV-Mecp2-/y and SOM-Mecp2-/y mice cannot be explained by regional differences in MeCP2 expression. It is, however, intriguing that MeCP2 may be more highly expressed in SOM+ neurons in the cortex, suggesting that MeCP2 expression levels may contribute to different properties of neuronal subtypes (Figure 1B). It is also worth noting that PV-Mecp2-/y mice developed a wide range of RTT-related features (motor, sensory, social, and cognitive deficits), while SOM-Mecp2-/y mice seemed to be deficient in the modulatory functions of inhibitory neurons, developing seizures and stereotypies. That PV-Mecp2-/y mice seem to be more severely affected could reflect the greater role of PV+ cells in suppressing pyramidal cell output (Atallah et al., 2012Atallah B.V. Bruns W. Carandini M. Scanziani M. Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli.Neuron. 2012; 73: 159-170Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar). The stronger neurological phenotype of PV-Mecp2-/y mice could also reflect the integral role of PV+ neurons in maintaining excitatory/inhibitory balance in the cortex, a role that SOM+ neurons do not share (Xue et al., 2014Xue M. Atallah B.V. Scanziani M. Equalizing excitation-inhibition ratios across visual cortical neurons.Nature. 2014; 511: 596-600Crossref PubMed Scopus (412) Google Scholar). Recent work by He et al. showed that loss of MeCP2 from PV+ neurons resulted in cells with immature neuronal properties, leading to decreased sensitivity to excitatory input (He et al., 2014He L.J. Liu N. Cheng T.L. Chen X.J. Li Y.D. Shu Y.S. Qiu Z.L. Zhang X.H. Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity.Nat. Commun. 2014; 5: 5036Crossref PubMed Scopus (73) Google Scholar); a Mecp2 null PV+ neuron may be unable to assess downstream excitatory neuronal activity and modulate its inhibitory activity appropriately. The authors also performed a limited number of behavioral analyses of mice lacking MeCP2 in PV+ cells, but their results showed only a mild ataxia and no effect on social interaction or cued memory. The more extensive phenotypes seen in our study are most likely due to the difference in the animal’s age: He et al. evaluated the mice at a younger age (8–10 weeks), while we studied them longitudinally over an extended period and observed memory and social deficits at 15 and 14 weeks, respectively. It is also important to consider the differences in expression patterns between the utilized Cre lines: He et al. used a Pvalb-IRES-Cre mouse line, which expresses Cre only in neurons that strongly express PV but does not cover a large population of more weakly PV-expressing neurons, such as those in the inner nuclei of the thalamus, which are targeted by the Pvalb-2A-Cre line used here (Madisen et al., 2010Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. et al.A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.Nat. Neurosci. 2010; 13: 133-140Crossref PubMed Scopus (3846) Google Scholar). It has been shown that cells expressing a low level of PV, including some layer 5 pyramidal cells, also express Cre in the Pvalb-2A-Cre line (Madisen et al., 2010Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. et al.A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.Nat. Neurosci. 2010; 13: 133-140Crossref PubMed Scopus (3846) Google Scholar), and we cannot exclude the possibility that some features observed were confounded by the deficit in layer 5 pyramidal cells. This possibility is unlikely, however, as CamKII-Cre; Mecp2flox/y mice (CamKII-Mecp2-/y) (Chen et al., 2001Chen R.Z. Akbarian S. Tudor M. Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.Nat. Genet. 2001; 27: 327-331Crossref PubMed Scopus (1032) Google Scholar, Gemelli et al., 2006Gemelli T. Berton O. Nelson E.D. Perrotti L.I. Jaenisch R. Monteggia L.M. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice.Biol. Psychiatry. 2006; 59: 468-476Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar), which lack Mecp2 in forebrain excitatory neurons, show only limited behavioral abnormalities, whereas Viaat-Mecp2-/y mice recapitulate the majority of RTT-related features without affecting Mecp2 expression in layer 5. In addition, Viaat- and PV-Mecp2-/y show increased social interaction, a severe motor deficit, but no anxiety, whereas CamKII-Mecp2-/y mice show anxiety, decreased social interaction, and only mild ataxia in the rotarod assay. Although neurological features in PV-Mecp2-/y and SOM-Mecp2-/y mice recapitulated the majority of behavioral deficits observed in Viaat-Mecp2-/y mice, this replication was not complete (Table 1 and Figure S3). It thus seems likely that either another inhibitory neuron subtype mediates the remaining three features or that synergistic impairment of multiple cell types is necessary for some RTT symptoms to appear. Some of the features absent from both PV-Mecp2-/y and SOM-Mecp2-/y mice could be attributed to the medium spiny neurons in the striatum, which are inhibitory projection neurons expressing Viaat but not PV or SOM, or to 5HT3a receptor-expressing inhibitory neurons, which constitute about 30% of the interneurons in the cortex but do not overlap with PV+ or SOM+ interneurons (Férézou et al., 2002Férézou I. Cauli B. Hill E.L. Rossier J. Hamel E. Lambolez B. 5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons.J. Neurosci. 2002; 22: 7389-7397Crossref PubMed Google Scholar, Rudy et al., 2011Rudy B. Fishell G. Lee S. Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.Dev. Neurobiol. 2011; 71: 45-61Crossref PubMed Scopus (837) Google Scholar). One subtype of 5HT3a receptor+ cells, vasoactive intestinal peptide-expressing cells, is activated during auditory discrimination tasks, whisking, and other behaviors and serves primarily to innervate SOM+ cells in the cortex to disinhibit local circuitry (Lee et al., 2013Lee S. Kruglikov I. Huang Z.J. Fishell G. Rudy B. A disinhibitory circuit mediates motor integration in the somatosensory cortex.Nat. Neurosci. 2013; 16: 1662-1670Crossref PubMed Scopus (448) Google Scholar, Pi et al., 2013Pi H.J. Hangya B. Kvitsiani D. Sanders J.I. Huang Z.J. Kepecs A. Cortical interneurons that specialize in disinhibitory control.Nature. 2013; 503: 521-524Crossref PubMed Scopus (665) Google Scholar). It would be of great interest to investigate the role of 5HT3a receptor+ cells in behavior and in the pathogenesis of RTT. The only common feature observed both in PV-Mecp2-/y and SOM-Mecp2-/y mice was early death, suggesting that robust function of both PV+ and SOM+ neurons are critical for survival (Figures 4D and 4E). Re-expressing MeCP2 only in PV+ or in SOM+ cells of Mecp2 null mice improves gross phenotypic score and survival rate, while such improvement is not observed in mice expressing MeCP2 only in the forebrain inhibitory neurons (Goffin et al., 2014Goffin D. Brodkin E.S. Blendy J.A. Siegel S.J. Zhou Z. Cellular origins of auditory event-related potential deficits in Rett syndrome.Nat. Neurosci. 2014; 17: 804-806Crossref PubMed Scopus (53) Google Scholar). Loss of MeCP2 in the brain stem and spinal cord causes abnormal respiration and heart rate and is associated with premature death (Ward et al., 2011Ward C.S. Arvide E.M. Huang T.W. Yoo J. Noebels J.L. Neul J.L. MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan.J. Neurosci. 2011; 31: 10359-10370Crossref PubMed Scopus (64) Google Scholar). It thus seems likely that PV+ or SOM+ cells in the hindbrain regions or the spinal cord are critical for normal lifespan, although the direct cause of premature lethality in Mecp2 null mice is still unclear. Further study is necessary to distinguish the physiological functions of PV+ and SOM+ cells in these brain regions. How does MeCP2 loss in PV+ and SOM+ cells lead to neurological deficit? Because MeCP2 regulates expression of glutamic acid decarboxylase (GAD), the phenotypes of PV- and SOM- Mecp2-/y mice may be caused by partial loss of GAD function (Chao et al., 2010Chao H.T. Chen H. Samaco R.C. Xue M. Chahrour M. Yoo J. Neul J.L. Gong S. Lu H.C. Heintz N. et al.Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.Nature. 2010; 468: 263-269Crossref PubMed Scopus (844) Google Scholar). This seems unlikely, as only a few features in the inhibitory neuron Mecp2 conditional knockout are present in GAD2 knockout mice, and other phenotypes do not overlap with either GAD1- or GAD2-deficient mice. While GAD1 knockout mice die postnatally from a severe reduction in GABA and cleft palate (Asada et al., 1997Asada H. Kawamura Y. Maruyama K. Kume H. Ding R.G. Kanbara N. Kuzume H. Sanbo M. Yagi T. Obata K. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase.Proc. Natl. Acad. Sci. USA. 1997; 94: 6496-6499Crossref PubMed Scopus (455) Google Scholar), GAD1 heterozygous mice are viable and have reduced sociability (Sandhu et al., 2014Sandhu K.V. Lang D. Müller B. Nullmeier S. Yanagawa Y. Schwegler H. Stork O. Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice.Genes Brain Behav. 2014; 13: 439-450Crossref PubMed Scopus (38) Google Scholar). GAD2 knockout mice are viable with only mild reduction in GABA and develop spontaneous seizures, anxiety-related features, impaired cued and contextual memory, and decreased prepulse inhibition (Heldt et al., 2004Heldt S.A. Green A. Ressler K.J. Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment.Neuropsychopharmacology. 2004; 29: 1610-1619Crossref PubMed Scopus (55) Google Scholar, Kash et al., 1997Kash S.F. Johnson R.S. Tecott L.H. Noebels J.L. Mayfield R.D. Hanahan D. Baekkeskov S. Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.Proc. Natl. Acad. Sci. USA. 1997; 94: 14060-14065Crossref PubMed Scopus (276) Google Scholar, Kash et al., 1999Kash S.F. Tecott L.H. Hodge C. Baekkeskov S. Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.Proc. Natl. Acad. Sci. USA. 1999; 96: 1698-1703Crossref PubMed Scopus (189) Google Scholar, Stork et al., 2003Stork O. Yamanaka H. Stork S. Kume N. Obata K. Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice.Genes Brain Behav. 2003; 2: 65-70Crossref PubMed Scopus (61) Google Scholar), but GAD2 heterozygotes are grossly normal (Heldt et al., 2004Heldt S.A. Green A. Ressler K.J. Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment.Neuropsychopharmacology. 2004; 29: 1610-1619Crossref PubMed Scopus (55) Google Scholar, Kash et al., 1997Kash S.F. Johnson R.S. Tecott L.H. Noebels J.L. Mayfield R.D. Hanahan D. Baekkeskov S. Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.Proc. Natl. Acad. Sci. USA. 1997; 94: 14060-14065Crossref PubMed Scopus (276) Google Scholar). Therefore, the behavioral effects must be due to some other cause beyond the partial reduction in GAD1/2 levels. MeCP2 binds to DNA genome-wide and regulates the expression of thousands of genes (Chahrour et al., 2008Chahrour M. Jung S.Y. Shaw C. Zhou X. Wong S.T. Qin J. Zoghbi H.Y. MeCP2, a key contributor to neurological disease, activates and represses transcription.Science. 2008; 320: 1224-1229Crossref PubMed Scopus (1363) Google Scholar, Skene et al., 2010Skene P.J. Illingworth R.S. Webb S. Kerr A.R. James K.D. Turner D.J. Andrews R. Bird A.P. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state.Mol. Cell. 2010; 37: 457-468Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar). It is thus likely that alteration of many genes in addition to GAD1/2 causes widespread neuronal dysfunction that leads to the behavioral effects of MeCP2 loss. In conclusion, our data indicate that individual inhibitory interneuron subtypes contribute to the RTT phenotype in a somewhat modular manner. Further characterization of the contribution of these two subtypes to behavior in health and disease should shed light on a number of neuropsychiatric conditions. A full description of methods is found in the Supplemental Experimental Procedures. A.I.-I., K.U., and H.Y.Z. conceived the project, designed the experiments, and wrote the manuscript. A.I.-I. and K.U. performed and analyzed the behavioral and histological experiments. H.C. and J.W.S. designed electrophysiological experiments that were performed by H.C. but are not shown in the paper. This research was supported by NIH/NINDS 5R01NS057819-08, the International Rett Syndrome Foundation (H.Y.Z.), the Japan Society for the Promotion of Science (A.I.-I.), NIH F32NS083137, NIH T325 HD055200 (K.U.), and NIH/1U54HD083092-01 (Neurovisualization, Neuroconnectivity and Neurobehavioral Cores) at the BCM Intellectual and Developmental Disabilities Research Center. H.Y.Z. is an investigator with the Howard Hughes Medical Institute. Download .pdf (.84 MB) Help with pdf files Document S1. Supplemental Experimental Procedures and Figures S1–S3 Download .xlsx (.04 MB) Help with xlsx files Table S1, Related to Figures 2, 3, and 4. Statistical Summary of the Behavioral Datahttps://www.cell.com/cms/asset/adb9a31a-d22b-41ad-adc9-32660d19eb53/mmc3.mp4Loading ... Download .mp4 (3.44 MB) Help with .mp4 files Movie S1, Related to Figure 4. SOM-Mecp2-/y Mice Develop SeizuresThe movie shows a seizure event that occurred in a 20-week-old SOM-Mecp2-/y mouse after it was transferred to a new cage." @default.
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• W2178727006 title "Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes" @default.
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