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In subjects with schizophrenia, audiologic, electrophysiologic, and structural imaging studies indicate abnormalities in auditory sensory processing localized to the auditory cortex of the superior temporal gyrus. Gray matter volume reductions in this region appear to be specific to schizophrenia and are present prior to treatment with antipsychotic medications. These volume reductions are correlated with electrophysiologic measures of auditory sensory processing, and with the cardinal symptoms of thought disorder and auditory hallucinations. In non-human primates, cortical processing of auditory input occurs both in parallel and in series through hierarchically organized auditory core, lateral belt, and parabelt cortices of the superior temporal gyrus. Feedforward projections (see schematic) from auditory core to lateral belt, and from lateral belt to parabelt, arise predominantly from layer 3 pyramidal cells and terminate in layers 3c/4 of the target region. Reciprocal feedback projections arise from both layers 3 and 5, and terminate predominantly in layer 1. Feedforward projections provide for rapid transfer of sensory information, facilitating pre-attentive behavioral responses. In contrast, attentional or top-down mechanisms, which provide for contextual interpretation of sensory input, are likely to be dependent on feedback connections. The deficit in precision of early auditory processing, observed in some subjects with schizophrenia, has been described as pre-attentive, suggesting a preferential vulnerability of feedforward circuits. Similarly, our initial studies of auditory cortex in subjects with schizophrenia have found reductions in pyramidal cell size and axon boutons in a laminar pattern indicative of alterations of feedforward, but not feedback, circuits (see Sweet et al 2004 and Sweet et al 2007).
Proper interpretation of these findings has been
limited by the lack of data regarding the correspondence between human auditory
association cortex and auditory regions defined in non-human primates, and by
the absence of unbiased methods for determination of pyramidal cell numbers and
size within specific cortical layers. We have been addressing both these issues,
in collaboration
Additional studies to quantify laminar changes in pre- and postsynaptic elements in subjects with schizophrenia are ongoing. For example, dendritic spines can be labeled with antibody to spinophilin (shown below) and quantified. Using this approach, we have found dendritic spine densities to be reduced by ~27% in deep layer 3 of primary auditory cortex in subjects with schizophrenia, and correlated with reductions in axon bouton densities in these subjects (see Sweet et al 2009). Currently we are using multiple label confocal microscopy to evaluate which specific populations of axon boutons appear to be affected in subjects with schizophrenia. Our preliminary findings suggest impairments in intracortical, rather than thalamocortical boutons.
Click to see enlarged image and caption These reductions in density of dendritic spines axon boutons likely contribute to the reduced auditory gray matter volume in subjects with schizophrenia and to an impaired spread of activation within the layer 3 pyramidal cell networks of the primary auditory cortex. Consistent with this interpretation, our preliminary data suggests that the correlated reductions of spine and axon bouton density are selective for excitatory intracortical, but not thalamacortical, boutons. Because dendritic spines remain plastic structures,
with a proportion arising and retracting through adulthood, net elimination
will result from reduced spine emergence/persistence and/or increased spine
retraction. This bidirectional balance is driven by long-term potentiation (LTP)
and long-term depression (LTD). LTP and LTD are varyingly engaged depending
on the precise timing of excitation relative to cell action potential
firing, timing that might be altered in layer 3 pyramidal cells of primary
auditory cortex due to deficits in the intracortical local inhibitory inputs
that control the temporal precision of their firing. LTP results in spine
enlargement and persistence via the induction of F-actin stabilization,
mediated by a Kalirin → Rac1→ PAK1 pathway. Thus, altered
Kalirin
expression results in deficits in spine emergence, in spine persistence,
and in LTP-induced spine enlargement. LTD results in destabilization of F-actin,
spine shrinkage, and elimination. Recently, the dendritic spine-specific F-actin
binding protein, spinophilin, has been shown to be a mediator of LTD and of
spine
Plasticity of Auditory Cortical Circuits In Schizophrenia We hypothesize that impaired auditory processing in subjects with schizophrenia reflects reductions in the intracortical, but not thalamocortical, excitatory circuits in layer 3 of primary auditory cortex, and arise due to shifts in the balance of LTP- and LTD-induced spine plasticity resulting in a net enhancement of spine elimination in intracortical circuits. This balance may be shifted due to effects of impaired layer 3 inhibitory circuits on spike timing and/or due to altered expression of plasticity mediators. However, selective reductions in intracortical circuits are most likely to require both of these effects. The Aims of this project are: 1) To determine if numbers of pre- and post-synaptic components of excitatory intracortical circuits are reduced in layer 3 of AI of subjects with schizophrenia. 2) To determine if numbers of inhibitory boutons are reduced in layer 3 of AI of subjects with schizophrenia. 3) To determine whether the expression of mediators of LTP-induced spine plasticity are altered in AI of subjects with schizophrenia. 4) To determine whether the expression of mediators of LTD-induced spine plasticity are altered in AI of subjects with schizophrenia. 5) To characterize the effects of altered expression of kalirin-7, spinophilin, and DARPP-32 on activity-dependent spine plasticity in a cell culture model. |
