The immature brain is not a small sized version of the adult brain: its circuits are profoundly different and much less understood. Therefore, studying how neural circuits take shape is essential for several reasons. First, it is important to understand how the normal brain works. Second, it is critical to gain insights into how abnormal brain development contributes to neurological and mental health disorders. Third and last, it is required for a rational approach to create novel therapeutic strategies for diseases that are currently untreatable. Cajal-Retzius cells are transient neurons that play important functions during mammalian corticogenesis, such as control of neuronal migration and cortical lamination. However, their fast network/computational roles, mediated by synaptic transmission, remain rather mysterious and poorly understood. Based on the work that we have already published and on the preliminary data collected during these last three and a half years of funding, we propose to test the overarching hypothesis that Cajal-Retzius cells of the developing hippocampus are an essential component of a microcircuit that is involved, physiologically, in the regulation of synaptic plasticity of specific hippocampal connections, but may also contribute to the well-known vulnerability of this region to seizures. This project has a direct translational relevance because a deeper understanding of cellular mechanisms involved in network functions of the maturing brain is critical to provide insights for novel therapeutic approaches in neurodevelopmental disorders.

Public Health Relevance

This proposal plans to test the broad hypotheses that: (i) Cajal-Retzius cells are critical neuronal elements controlling the plasticity/maturation of an earl hippocampal microcircuit, physiologically associated with spatial memory functions and (ii) may play a role in the well-known vulnerability of young animals to epilepsy. The identification of cel type-specific mechanisms of neuronal development is critical to gain insights into how neural circuits take shape and how abnormal network activity contributes to neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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Northwestern University at Chicago
Schools of Medicine
United States
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Anstötz, Max; Huang, Hao; Marchionni, Ivan et al. (2016) Developmental Profile, Morphology, and Synaptic Connectivity of Cajal-Retzius Cells in the Postnatal Mouse Hippocampus. Cereb Cortex 26:855-72
Anstötz, Max; Cosgrove, Kathleen E; Hack, Iris et al. (2014) Morphology, input-output relations and synaptic connectivity of Cajal-Retzius cells in layer 1 of the developing neocortex of CXCR4-EGFP mice. Brain Struct Funct 219:2119-39
Quattrocolo, Giulia; Maccaferri, Gianmaria (2014) Optogenetic activation of cajal-retzius cells reveals their glutamatergic output and a novel feedforward circuit in the developing mouse hippocampus. J Neurosci 34:13018-32
Quattrocolo, Giulia; Maccaferri, Gianmaria (2013) Novel GABAergic circuits mediating excitation/inhibition of Cajal-Retzius cells in the developing hippocampus. J Neurosci 33:5486-98
Marchionni, Ivan; Beaumont, Michael; Maccaferri, Gianmaria (2012) The chemokine CXCL12 and the HIV-1 envelope protein gp120 regulate spontaneous activity of Cajal-Retzius cells in opposite directions. J Physiol 590:3185-202
Cosgrove, Kathleen E; Maccaferri, Gianmaria (2012) mGlu1ýý-dependent recruitment of excitatory GABAergic input to neocortical Cajal-Retzius cells. Neuropharmacology 63:486-93
Maccaferri, Gianmaria (2011) Modulation of hippocampal stratum lacunosum-moleculare microcircuits. J Physiol 589:1885-91
Maccaferri, Gianmaria (2011) Microcircuit-specific processing in the hippocampus. J Physiol 589:1873-4
Marchionni, Ivan; Takacs, Virag T; Nunzi, Maria Grazia et al. (2010) Distinctive properties of CXC chemokine receptor 4-expressing Cajal-Retzius cells versus GABAergic interneurons of the postnatal hippocampus. J Physiol 588:2859-78