Neural circuit assembly and mental health
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Image shows a coronal section of adult mouse dentate gyrus (DG). Green labels neural stem cells (NSCs) and progenitorcells, purple labels astrocytes, and blue labels nuclei in the granule cell layer (GCL).

Immune-mediated nervous system repair
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Image shows a section of adult mouse sciatic nerve seven days after crush injury. The distal segment of the nerve undergoes Wallerian degeneration. Myelin ovoid form as myelin sheaths disintegrate (labeled green with Fluoromyelin). Schwann cells (Axons) stained with anti-S100 (SCG10) are labeled red. Cell nuclei, stained with Hoechst nuclear dye, are labeled blue.

Myelin development and axon remyelination following injury
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Image shows a Dorsal root ganglion (DRG) section of adult mouse two weeks after AAV2-GFP injection in the sciatic nerve. Three days prior to DRG collection, the sciatic nerve was subjected to crush injury (a procedure called conditioning injury). Staining: GFP-green, Red- Neurofilament, Blue- DLK.

Inhibitors of synaptic strength
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Image shows dissociated hippocampal neurons isolated from E18 rat brain and cultured for 15 days in vitro. Cultures were stained under non-permeabilizing conditions for the AMPA receptor subunit GluA1 (red) and Nogo-A (green). Following detergent treatment, cultures were stained for MAP2 (magenta) to delineate dendrites. DAPI (blue) was used to stain nuclei.

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Neural circuit assembly and mental health

During brain development, abnormal network assembly or refinement of neural circuits leads to neuronal dysconnectivity and is believed to be an important factor in causing behavioral deficits and cognitive symptoms associated with psychosis. Over the past three decades, enormous progress has been made in understanding the function of axon guidance molecules and their role in circuit assembly and refinement. Applying this wealth of knowledge to neuro-developmental disorders is expected to provide important insights into disease ethology, a critical step toward improving treatments and outcomes for patients with psychiatric disorders. An increasing number of molecular lesions in patients with psychosis, (e.g. autism and schizophrenia) are associated with genes that function in axon guidance, synapse assembly and glutamatergic neurotransmission. This includes genetic variations in SEMAPHORIN and PLEXIN (PLXN) genes, underscoring the importance of braindevelopment in disease etiology. A long-term goal of our studies is to gain insights into which signaling pathways and neural circuits are perturbed by SEMA/PLXN mutations that lead to deficits in complex behavior.

Image shows a coronal section of adult mouse dentate gyrus (DG). Green labels neural stem cells (NSCs) and progenitorcells, purple labels astrocytes, and blue labels nuclei in the granule cell layer (GCL).

Immune-mediated nervous system repair

Following injury to the adult mammalian central nervous system (CNS), severed axons fail to undergo spontaneous regeneration. The limited and transient growth response of injured CNS neurons is in part responsible for poor clinical outcomes following brain or spinal cord trauma. We use three different surgical procedures to study axon regeneration in the injured adult mouse CNS, (i) retro-orbital optic nerve crush injury, (ii) transection of the dorsal columns in the spinal cord and (iii) unilateral transection of the pyramids. Ongoing research is focused on nervous system – immune system interaction. The nervous system and immune system are in constant dialogue; this interaction is of particular interest following CNS injury or disease, as modulation of the inflammatory milieu can profoundly influence neuronal survival, axonal regeneration, myelination and neurological outcomes. We recently showed that engagement of the pattern recognition receptor dectin-1/CLEC7A on innate immune cells facilitates robust axonal growth in the injured mouse optic nerve. A challenge in immune-mediated neurorepair is the occurrence of bystander toxic effects that often mask beneficial (pro-regenerative) functions. A major goal of ongoing research is to dissect the pro-regenerative and neurotoxic effects of inflammation at the molecular level. A detailed understanding of these opposing effects is required in order to maximize pro-regenerative pathways, and at the same time, block detrimental aspects of neuroinflammation.

Image shows a section of adult mouse sciatic nerve seven days after crush injury. The distal segment of the nerve undergoes Wallerian degeneration. Myelin ovoid form as myelin sheaths disintegrate (labeled green with Fluoromyelin). Schwann cells (Axons) stained with anti-S100 (SCG10) are labeled red. Cell nuclei, stained with Hoechst nuclear dye, are labeled blue.

Myelin development and axon remyelination following injury

In the vertebrate CNS, the majority of long axons are myelinated. Myelin greatly increases the conduction velocity of action potentials and provides metabolic support for axons. Bidirectional axo-glial signaling is critical for nervous system myelination and fiber stability. We study the role of phosphoinositides, a group of signaling lipids, during developmental myelination and axon remyelination following myelin injury. The myelin producing cells in the CNS are the oligodendrocytes (OLs). Typically, OLs have complex morphologies, and each cell can segmentally myelinate up to 50 axons. OLs produce the myelin building blocks inside their cell bodies following instructions encoded by genes within the nucleus. However, the signals that regulate the trafficking of these components to the myelin sheath are poorly understood. We found that in transgenic mice perturbation of the biosynthetic complex for the phosphoinositide PI(3,5)P2 in neurons or in the oligodendrocyte progenitor cells (OPCs) causes severe CNS hypomyelination and impaired conduction of action potentials. Primary OLs with reduced levels of PI(3,5)P2 accumulate large LAMP1+ and Rab7+ vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P2 deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1+ perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P2 synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endo-lysosomal system in primary cells and brain tissue. A key next step will be to identify the regulatory mechanisms that control the production of PI(3,5)P2 in OLs and neurons and to define how exactly PI(3,5)P2 regulates intracellular membrane trafficking.​

Image shows a Dorsal root ganglion (DRG) section of adult mouse two weeks after AAV2-GFP injection in the sciatic nerve. Three days prior to DRG collection, the sciatic nerve was subjected to crush injury (a procedure called conditioning injury). Staining: GFP-green, Red- Neurofilament, Blue- DLK.

Inhibitors of synaptic strength

Adult CNS white matter is a rich source of growth inhibitory molecules, including the CNS regeneration inhibitors Nogo, MAG and OMgp. The physiological role of CNS regeneration inhibitors in the naïve (uninjured) brain has been a mystery for many years. Nogo-A and OMgp are abundantly expressed by mature neurons and found along dendrites and synaptic profiles. To assess potential roles in synaptic transmission, we conducted electro-physiological recordings

from hippocampal slices acutely prepared from wildtype and mice

deficient for the Nogo receptor (NgR1). We found that NgR1 and its ligands Nogo and OMgp function as negative regulators of activity-dependent neurotransmission. Our ultrastructural studies further revealed that NgR1 not only regulates synaptic strength but also controls the shape of dendritic spines and the density of excitatory synapses in the hippocampus. Ongoing studies focus on the signaling pathways regulated by CNS regeneration inhibitors and their receptors to negatively regulate synaptic strength.

Image shows dissociated hippocampal neurons isolated from E18 rat brain and cultured for 15 days in vitro. Cultures were stained under non-permeabilizing conditions for the AMPA receptor subunit GluA1 (red) and Nogo-A (green). Following detergent treatment, cultures were stained for MAP2 (magenta) to delineate dendrites. DAPI (blue) was used to stain nuclei.