Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

Several neuropsychiatric disorders are associated with cognitive and social dysfunction. Post-mortem studies of patients with schizophrenia have revealed specific changes in area CA2, a long over-looked region of the hippocampus recently found to be critical for social memory formation. To examine how area CA2 is altered in psychiatric illness, we used the Df(16)A+/− mouse model of the 22q11.2 microdeletion, a genetic risk factor for developing several neuropsychiatric disorders, including schizophrenia. We report several age-dependent CA2 alterations: a decrease in the density of parvalbumin-stained interneurons, a reduction in the amount of feed-forward inhibition and a change in CA2 pyramidal neuron intrinsic properties. Furthermore, we found that area CA2 is less plastic in Df(16)A+/− mice, making it nearly impossible to evoke action potential firing in CA2 pyramidal neurons. Finally, we show that Df(16)A+/− mice display impaired social cognition, providing a potential mechanism and a neural substrate for this impairment in psychiatric disorders.

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.

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