Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction
| Autor: | David Fleck, Ileana L. Hanganu-Opatz, Lingzhen Song, Peggy Putthoff, Xiaxia Xu, Marc Spehr |
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| Rok vydání: | 2022 |
| Předmět: |
Male
medicine.medical_specialty hippocampus Hippocampus Mice Transgenic Hippocampal formation Optogenetics Biology network oscillations Mice Systems/Circuits Risk Factors medicine Animals ddc:610 mouse model of psychiatric risk Effects of sleep deprivation on cognitive performance Psychiatry Prefrontal cortex development Research Articles axonal projections prefrontal cortex Mental Disorders General Neuroscience Excitatory Postsynaptic Potentials Cognition Mice Inbred C57BL Disease Models Animal Animals Newborn Flip Excitatory postsynaptic potential Female Gene-Environment Interaction Nerve Net axonal projections development hippocampus mouse model of psychiatric risk network oscillations prefrontal cortex |
| Zdroj: | PubMed Central ZENODO ORCID Microsoft Academic Graph The Journal of Neuroscience The journal of neuroscience 42(4), 601-618 (2022). doi:10.1523/JNEUROSCI.1203-21.2021 |
| DOI: | 10.5281/zenodo.6532406 |
| Popis: | Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development. SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders. This work was supported by grants from the European Research Council (ERC-2015-CoG 681577 to I.L.H.-O.), German Research Foundation (Ha4466/11-1, SPP 1665, and SFB 936 B5 to I.L.H.-O; 368482240/GRK2416, 302153259, and 378028035 to M.S.), Horizon 2020 DEEPER 101016787, and Landesforschungsförderung Hamburg (LFF73 and LFF76 to I.L. H.-O.). We thank Dr. Joseph Gogos for providing the DISC1 mice. We also thank A. Marquardt and A. Dahlmann for excellent technical assistance. |
| Databáze: | OpenAIRE |
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