A spectrum of diseases, both psychiatric and neurological in nature, involve long term progressive changes that may well begin in the earliest phases of brain development. The symptoms of schizophrenia, Tourette's syndrome, Parkinson's disease and Huntington's chorea, may emerge from defects in the anatomical organization of the basal ganglia that result in disordered neurochemical function. The underlying neuropathology appears to involve the striatum (caudate and putamen), a key structure of the basal ganglia- that is characterized by a dense dopaminergic innervation and a compartmentalized distribution of intrinsic neurons. Studies described here will focus on the development of the anatomical organization of this structure, attempting to dissociate those aspects that are intrinsically specified by the striatal neurons, as opposed to those directed by the ingrowth of dopaminergic afferents that occurs very early in life.
The aim of the present proposal is to provide an anatomical basis for understanding how interference with the proper development of this key structure may lead to disordered functioning later in life. As a foundation for studying the behavioral consequences of pathological development, it is necessary to understand the factors involved in guiding the normal development of the striatum. The specific experiments involve a temporal and spatial analysis of the development of several cell types found within the striatum, defined immunocytochemically on the basis of their neurotransmitter phenotype. Experimental manipulations will be made it order to perturb the normal development of the distinctive striatal compartmentalization now known to exist. The effects of early removal of dopamine input on striatal development and organization will be assessed both in vivo and in transplanted striatal tissue. Other rats will be treated in utero with an antimitotic agent timed so as to kill a select population of striatal neurons, and the resultant consequences on the development of other cells and afferents to the striatum assessed. These studies are expected to reveal ways in which genetic defects or neurotoxic insults produce alterations in anatomical development of the striatum that result in long-lasting abnormalities in basal ganglia organization and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH046577-05
Application #
2445494
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1991-09-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
110521739
City
Menands
State
NY
Country
United States
Zip Code
12204
Snyder-Keller, Abigail; Chandra, Ruchira; Lin, Yili et al. (2002) Basal EGR-1 (zif268, NGFI-A, Krox-24) expression in developing striatal patches: role of dopamine and glutamate. Brain Res 958:297-304
Snyder-Keller, A; Costantini, L C; Graber, D J (2001) Development of striatal patch/matrix organization in organotypic co-cultures of perinatal striatum, cortex and substantia nigra. Neuroscience 103:97-109
Costantini, L C; Snyder-Keller, A (1997) Co-transplantation of fetal lateral ganglionic eminence and ventral mesencephalon can augment function and development of intrastriatal transplants. Exp Neurol 145:214-27
Snyder-Keller, A; Costantini, L C (1996) Glutamate receptor subtypes localize to patches in the developing striatum. Brain Res Dev Brain Res 94:246-50
Aronica, E; Costantini, L C; Snyder-Keller, A (1996) Reciprocal influences of nigral cells and striatal patch neurons in dissociated co-cultures. J Neurosci Res 44:540-50
Snyder-Keller, A M (1995) The development of striatal patch/matrix organization after prenatal methylazoxymethanol: a combined immunocytochemical and bromo-deoxy-uridine birthdating study. Neuroscience 68:751-63
Costantini, L C; Vozza, B M; Snyder-Keller, A M (1994) Enhanced efficacy of nigral-striatal cotransplants in bilaterally dopamine-depleted rats: an anatomical and behavioral analysis. Exp Neurol 127:219-31
Snyder-Keller, A M; Keller Jr, R W (1993) Prenatal cocaine increases striatal serotonin innervation without altering the patch/matrix organization of intrinsic cell types. Brain Res Dev Brain Res 74:261-7