Joseph Gogos, M.D., Ph.D.

Research Summary
Genetic analysis of processing and integration of sensory information.

Our interest in neural stem cells stems from one of the most interesting properties of olfactory sensory neurons (OSNs), that is their capacity to regenerate throughout the life of an organism. Newly born neurons must be able to find their appropriate target in the olfactory bulb since the map does not change as a function of the age of the organism. This regenerative capacity affords the possibility of significant plasticity but poses the question of how precise connections between the periphery and the brain are continually maintained to preserve the integrity of the sensory map. In one model, guidance mechanisms that are operative during development persist during adult life to guide the precise placement of newly generated axons. An alternative model argues that the mechanisms for precise targeting differ during development and regeneration. The simplest form of this model argues that pre-existent fibers of a given OSN population associate with identical regenerating projections perhaps through homophilic interactions, to assure the restoration of the map. Several recent experiments addressed these two broad models: We previously used regulated expression of diphtheria toxin in a specific subpopulation of sensory neurons to effect temporally controlled and spatially defined cell killing of OSNs expressing the P2 receptor . We found that following genetic ablation, newly formed projections return to the location of the original P2 glomeruli with no evidence for stray fibers at other locations in the bulb. This result is consistent with the second model that invokes the persistent presence of spatially defined guidance cues elaborated in the bulb. Additional and complementary experiments performed by other groups addressed the consequences of the synchronous death of all OSNs on the reformation of an olfactory map. In these experiments, the death of the bulk of OSNs has been effected either by chemical treatment of the peripheral sensory epithelium or by axotomy. In both cases, significant errors occur during the reinnervation of the bulb at all levels at which the projection is organized. Because each of these procedures introduces severe anatomical abnormalities and indiscriminately affects both neuronal and non-neuronal populations, reformation of the map is difficult to interpret.

Clearly, the functional significance of renewal in other brain regions will depend upon the ability of newly regenerated cells to form connections to appropriate targets. The observation that olfactory sensory neurons are continually generated in the periphery and that central synapses can reform with precision to regenerate a complex topographic map in the olfactory may provide insight into the fidelity of synapse formation after regeneration in other brain regions.

Our effort to understand whether synapses can reform with precision in the adult olfactory system has implications for other renewal processes in the central nervous system (CNS), since it may provide valuable insight into the fidelity of synapse formation after regeneration in other brain regions or the use of stem cells to cure neurological and neuro-psychiatric disorders.

1. Gogos JA, Osborne J, Nemes A, Mendelsohn M, Axel R. Genetic Ablation and Restoration of the Olfactory Topographic Map. Cell, 103, 609-620 (2000).

2. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 99(6):3717-22 (2002)

3. Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, Hyttinen J, Mannisto PT. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci. 15(2):246-56 (2002)

4. Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ, Roos JL, Rapoport JL, Gogos JA, Karayiorgou M. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 99(26):16859-64 (2002)

5. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci U S A. 100(15):8993-8 (2003)

6. Abecasis GR, Burt R, Hall D, Bochum S, Doheny KF, Lundy SL, Torrington M, Roos JL, Gogos JA, Karayiorgou M. Genome-wide scan in schizophrenia families from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. Am J Hum Genet. (in press)

1. We are using powerful techniques that permit us to control the survival and synaptic transmission of specific subsets of olfactory neurons in a temporally and spatially regulated manner, to investigate a) how precise connections between the periphery and the brain are continually maintained to preserve the integrity of the olfactory sensory maps, b) to examine whether there is modularity in the assembly of these maps and c) to probe the role of activity-dependent plasticity in the establishment, maintenance, and refinement of the olfactory sensory projections.
Burroughs Wellcome Fund (PI: Gogos) 9/1/01 - 8/31/04
The Whitehall Foundation (PI: Gogos) 7/1/03 - 6/30/06
NIH R01 (PI: Gogos) 7/1/03 - 6/30/07

2 We are also collaborating with Dr. Karayiorgou’s lab at Rockefeller University to follow-up genetic findings from families afflicted with schizophrenia and other psychiatric disorders, by generating transgenic mouse lines for candidate susceptibility genes in order to a) strengthen or weaken our hypotheses for a role of these genes in disease susceptibility and b) facilitate understanding of the function of these genes and how they may impact on the development of psychiatric disorders
New York City Council Speaker’s Fund (PI: Gogos) 6/1/02 - 5/31/05
McKnight Endowment Fund for Neuroscience (PI: Gogos) 2/1/03 - 1/31/06
The EJLB Foundation (PI: Gogos) 1/1/03 - 12/31/06
NARSAD (PI: Gogos) 7/1/03 - 6/30/05
NIH R01 (PI: Karayiorgou) 7/1/03 - 6/30/07 Subcontract (PI: Gogos)

3. AKT signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders1. Recently, we provided evidence that alterations in AKT1 signaling al so contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene (submitted). There are several possible mechanisms by which altered AKT1 function could influence the formation and function of neuronal circuits whose integrity is necessary to prevent progression to psychosis. This influence may be additive, perhaps due to small impairment of several processes, or may be restricted to a small number of key processes that are particularly AKT-dosage dependent. We are collaborating with Dr. Karayiorgou’s lab at Rockefeller University using AKT1-deficient mice to clarify the nature of the impairment and the neuronal pathways involved.
New York City Council Speaker’s Fund (PI: Gogos) 6/1/02 - 5/31/05

1997-2004: Burroughs Wellcome Fund Career Award in Neuroscience
2003-2006: McKnight Neuroscience of Brain Disorders Award, 2003
2003-2006: EJLB Scholar, 2003

Neural Stem Cell Scientific Oversight Committee
Physiology Faculty Search Committee
Developmental Neuroscience Search Committee