Neuropsychiatric disorders like schizophrenia, autism and bipolar disorder may be caused by changes in the maturation of connections between brain cells of the cerebral cortex during development. In mouse neocortex, we and others have shown that the 2nd postnatal week is a time when dendritic spines become stabilized, the density of synapses increases dramatically, and spontaneous activity becomes abruptly desynchronized. This is also a period when most Cajal-Retzius (CR) cells undergo cell death, although we recently showed that a small subset survives into adulthood. Although CR cells are well-known for their critical role in cortical lamination much less is known about their function as neurons. Indeed, considering that CR neurons are spontaneously active, fire synchronously, and make synapses with apical dendrites of pyramidal neurons, we envision that they might function as pacemakers of cortical network activity. Specifically, we propose to test the hypothesis that postnatal CR neurons can trigger synchronous activity in neocortex and that those that survive into adulthood continue to influence pyramidal neuron firing. Previous work in brain slices has been unable to demonstrate that CR neurons and pyramidal neurons are functionally connected probably because the integrity of axons and dendrites was disrupted. We intend to overcome this shortcoming by using in vivo two-photon Ca2+ imaging and electrophysiology to record from these cell types in the intact brain. We have identified a specific promoter for CR neurons that will allow us not only to specifically visualize these cells in Layer 1 but also to conditionaly express channel-rhodopsin using viral vectors and a Cre-Lox approach. In the first aim, we will examine morphological and electrophysiological properties of CR neurons at early postnatal vs. adult stages to determine whether surviving CR neurons in mature animals are distinct from those that are destined to die during early development. In the second aim, we intend to modulate the firing of cohorts of CR neurons with optogenetics while recording from their synaptic partners in deeper cortical layers. The goal is to test whether CR neurons can influence the firing of pyramidal neurons and contribute to the emergence of synchronous network activity in the developing neocortex. These experiments will lay the foundation for future studies exploring the mechanisms by which dysfunction of CR neurons could cause neuropsychiatric diseases.

Public Health Relevance

The underlying brain defects that give rise to human neuropsychiatric diseases such as autism, bipolar disorder, epilepsy, and schizophrenia are not well understood. The proposed studies will investigate how one type of cell in the cerebral cortex, Cajal-Retzius neurons, plays a role in modulating the activity of burgeoning circuits in th brain. We will study areas important for emotion, cognition and creativity, as well as learning and memory. The experiments are designed to generate new ideas about how subtle alterations in communication between neurons could result in devastating neuropsychiatric disorders for which we still lack adequate treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH100614-02
Application #
8641437
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Panchision, David M
Project Start
2013-04-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$173,250
Indirect Cost
$60,750
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095