SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional upand downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.(A) Illustration of the callosal axon pathway of neurons residing at L2/3, electroporated with EGFP at E15.5 and assayed at P8.5 (top). Lower panel shows EGFPlabeled neurons (green) and NeuN (red). Representative images (bottom) are composites of more than one image acquired from one brain section under identical scanning parameters. Scale bar, 100 mm. (B) Representative images of contralateral axon terminal branching of EGFP-labeled neurons from coronal sections of P8.5 brains in utero electroporated at E15.5. Images are composites of more than one image acquired from one brain section under identical scanning parameters. Scale bar, 50 mm. (C) Tracings of representative neurons in in utero electroporated brains expressing EGFP at P8.5 from similar sections as in (B). Depicted are 2D projections of the axon terminal in the contralateral cortical L1-L4. Primary (blue), secondary (red), and tertiary (pink) branches from axons (green) are highlighted. Scale bar, 20 mm. (D) Quantitative assessment of contralateral axon branching in L1-L4 reveals a reduction of branch number in Setd1a +/À mice. (E) Representative images of axonal deficits in Setd1a +/À cortical neurons expressing EGFP at DIV5. Scale bar, 50 mm. (F-I) Reduction of (F) primary branch points in Setd1a +/À neurons (N = 4, n = 315) compared to WT neurons (N = 4, n = 304, p < 0.001), (G) total branch points in Setd1a +/À (N = 4, n = 315) compared to WT neurons (N = 4, n = 304, p < 0.0009), (H) primary axon length at DIV5 in Setd1a +/À (N = 4, n = 315) compared to WT neurons (N = 4, n = 304, p < 0.0008), and (I) total axon length in Setd1a +/À (N = 4, n = 315) compared to WT neurons (N = 4, n = 304, p < 0.0003).

SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutationof the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.

Kaminer J, Thakur P, Evinger C. Effects of subthalamic deep brain stimulation on blink abnormalities of 6-OHDA-lesioned rats. J Neurophysiol 113: 3038 -3046, 2015. First published February 11, 2015 doi:10.1152/jn.01072.2014.-Parkinson's disease (PD) patients and the 6-hydroxydopamine (6-OHDA) lesioned rat model share blink abnormalities. In view of the evolutionarily conserved organization of blinking, characterization of blink reflex circuits in rodents may elucidate the neural mechanisms of PD reflex abnormalities. We examine the extent of this shared pattern of blink abnormalities by measuring blink reflex excitability, blink reflex plasticity, and spontaneous blinking in 6-OHDA lesioned rats. We also investigate whether 130-Hz subthalamic nucleus deep brain stimulation (STN DBS) affects blink abnormalities, as it does in PD patients. Like PD patients, 6-OHDA-lesioned rats exhibit reflex blink hyperexcitability, impaired blink plasticity, and a reduced spontaneous blink rate. At 130 Hz, but not 16 Hz, STN DBS eliminates reflex blink hyperexcitability and restores both short-and long-term blink plasticity. Replicating its lack of effect in PD patients, 130-Hz STN DBS does not reinstate a normal temporal pattern or rate to spontaneous blinking in 6-OHDA lesioned rats. These data show that the 6-OHDA lesioned rat is an ideal model system for investigating the neural bases of reflex abnormalities in PD and highlight the complexity of PD's effects on motor control, by showing that dopamine depletion does not affect all blink systems via the same neural mechanisms.

Up-regulation of Mirta22/Emc10 is a major transcriptional effect of the 22q11.2-associated microRNA dysregulation and underlies key cellular as well as behavioral deficits. EMC10 is a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. Here we show that EMC10 expression is elevated in hiPSC-derived neurons from 22q11.2 deletion carriers and that reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling. Moreover, using injection of Antisense Oligonucleotides, we demonstrate that normalization of Emc10 levels in adult mouse brain rescues social memory deficits. The observations that elevated EMC10 expression is deleterious in 22q11.2 deletion carriers and that sustained elevation of EMC10 throughout the adult life can interfere with neural processes point to manipulations of EMC10 levels and downstream targets as a specific venue to ameliorate or even prevent disease progression in 22q11.2 deletion syndrome.

The synchronized beta band oscillations in the basal ganglia-cortical networks in Parkinson's disease (PD) may be responsible for PD motor symptoms or an epiphenomenon of dopamine loss. We investigated the causal role of beta band activity in PD motor symptoms by testing the effects of beta frequency subthalamic nucleus deep brain stimulation (STN DBS) on blink reflex excitability, amplitude, and plasticity in normal rats. Delivering 16 Hz STN DBS produced the same increase in blink reflex excitability and impairment in blink reflex plasticity in normal rats as occurs in rats with 6-OHDA lesions and PD patients. These deficits were not an artifact of STN DBS because when these normal rats received 130 Hz STN DBS, their blink characteristics were the same as without STN DBS. To demonstrate the blink reflex disturbances with 16 Hz STN DBS were frequency specific, we tested the same rats with 7 Hz STN DBS, a theta band frequency typical of dystonia. In contrast to beta stimulation, 7 Hz DBS exaggerated blink reflex plasticity as occurs in focal dystonia. Thus, without destroying dopamine neurons or blocking dopamine receptors, frequency specific STN DBS can be used to create PD- or dystonic-like symptoms in a normal rat.