Schizophrenia is associated with a reduction in GABA synthesis in a subpopulation of cortical interneurons that express the calcium-binding protein, parvalbumin (PV). These inhibitory interneurons display fast-spiking properties and target the perisomatic domain and axon initial segment of excitatory pyramidal neurons, thus enabling exquisite control over their spike timing. A deficit in such perisomatic inhibition in schizophrenia is likely to contribute to the impairments of fast cortical network synchronization and higher cognitive processing, which are key features of this disabling mental disorder. Another distinguishing characteristic of cortical PV interneurons are the dense aggregates of extracellular matrix molecules that ensheath their somata and primary processes, appearing as perineuronal nets (PNNs). The formation and degradation of these PNNs are activity-dependent, but their function and modulation in schizophrenia remain unknown. Our hypotheses are that 1) PV interneuron plasticity in schizophrenia is related to structural remodeling of PNNs, and 2) dysfunction of reciprocal inhibition between PV interneurons, possibly secondary to the altered structure of PNNs, is a key component of GABAergic deficits in schizophrenia. We will use two recently characterized transgenic mouse models of schizophrenia: the tamoxifen-inducible expression of the dominant-negative DISC1 C-terminal fragment (DISC1-cc) in 1-CaMKII expressing neurons and the selective knockout of NMDA receptors in forebrain GABAergic interneurons (Ppp1r2-Cre x NR1loxP/loxP mice). The ultrastructure of PNNs surrounding afferent terminals on PV interneurons will be determined using stimulated emission depletion (STED) super-resolution microscopy (nanoscopy) in fixed tissue. A deficiency in the inhibitory output of cortical PV interneurons in schizophrenia is thought to lead to hyperactivity and hyposynchrony of excitatory pyramidal neurons, and contribute to deficits in cognitive function. PV interneurons also show dense reciprocal connectivity, but the possible pathophysiology of such mutual inhibition remains unexplored. Patch-clamp recordings from PV interneurons in vitro will elucidate how these multiple modes of reciprocal GABAergic signaling and intrinsic membrane properties are modified in mouse models of schizophrenia. We propose that remodeling of the PNNs surrounding PV interneurons, and the erosion of compartmentalized synaptic and extrasynaptic GABAergic signaling pathways are critical components of the cortical network disinhibition in schizophrenia. Understanding how the multiple facets of GABAergic inhibition are disturbed in schizophrenia is essential for the rational design of GABAergic therapeutics. Moreover, elucidating the particular role of PNNs in both the function and dysfunction of PV interneurons should inspire new treatment strategies targeting the proteases responsible for PNN degradation.

Public Health Relevance

Schizophrenia is a debilitating mental disorder that affects ~2.4 million Americans, and ~1% of the world's adult population. This syndrome is thought to arise through an interaction of multiple genetic and environmental factors during brain development, leading to a persistent dysfunction of dopaminergic, glutamatergic, GABAergic and cholinergic neurotransmitter systems into adulthood. Current monoaminergic treatments for schizophrenia are most effective in treating positive symptoms, comprising hallucinations and/or delusions. However, such antipsychotics yield little amelioration of the burden of negative symptoms and cognitive impairments, which may have the greatest impact on patients'long-term social and occupational abilities. It has been suggested that cognitive dysfunction in schizophrenia might be more intimately linked with deficits in cortical GABAergic transmission. There is great potential for addressing such dysfunction, as GABAA receptors display a high degree of heterogeneity in subunit composition, which is reflected in distinct patterns of expression across cell types and brain regions, and confers the opportunity for selective pharmacological modulation. The rational design of GABAergic therapeutics, though, will require a more detailed understanding of how functional imbalances in the multiple facets of GABAA receptor-mediated signaling contribute to schizophrenic symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH092647-02
Application #
8263756
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2011-05-10
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$192,500
Indirect Cost
$67,500
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
Engel Jr, Jerome; Thompson, Paul M; Stern, John M et al. (2013) Connectomics and epilepsy. Curr Opin Neurol 26:186-94