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
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
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,
Dr. David Lewis at the University of Pittsburgh and Drs. Hans Jørgen Gundersen
and Karl-Anton Dorph-Petersen of
the University of Aarhus in Denmark. In non-human primate, auditory core,
lateral belt, and parabelt regions can be distinguished by differing
cytoarchitecture and intensity of staining for the calcium binding protein,
parvalbumin, and for the enzyme, acetylcholinesterase. We recently reviewed the
defining criteria for primary auditory (core) cortex, lateral belt cortex, and parabelt
cortex using these
methods in monkeys, and identified an additional division of the parabelt into
internal and external subregions, as shown in the figure at right.
also evaluated the performance of these criteria in
parcellating human auditory cortex, and found they could be applied
with high precision. (Follow links for examples of the
staining for the human auditory cortical
regions). A summary diagram of the locations of the auditory core, lateral belt,
and parabelt in the left superior temporal gyrus of humans, and the location of
the adjacent non-auditory Tpt, is shown at right.
Additional studies to quantify laminar changes in pre- and postsynaptic elements
in subjects with schizophrenia are ongoing. For example,
spines can be labeled with antibody to spinophilin
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
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
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
structural plasticity, via recruitment of the RhoA guanine nucleotide
exchange factor (GEF), Lfc, into spines, and via targeting of protein
phosphatase 1 (PPP1) to glutamate receptors within spines and to actin.
These findings have led us to develop a
model of spine loss in
schizophrenia that we are currently testing.
Plasticity of Auditory Cortical Circuits In
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
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.
To determine if
numbers of inhibitory boutons are reduced in layer 3 of AI of subjects with
To determine whether
the expression of mediators of LTP-induced spine plasticity are altered in AI of
subjects with schizophrenia.
To determine whether the expression of mediators of LTD-induced spine plasticity
are altered in AI of subjects with schizophrenia.
To characterize the effects of altered expression of kalirin-7, spinophilin,
and DARPP-32 on activity-dependent spine plasticity in a cell culture model.