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Updated 18 January 2010 E-mail discussion
Printable version

Live Discussion: Hippocampus in Schizophrenia Roundtable

Anthony Grace

Stephan Heckers

On Monday, 16 November 2009, Anthony Grace and Stephan Heckers led a live discussion.

The hippocampus has been a focus of increasing interest in the schizophrenia research community since the 1980s (Heckers and Konradi, 2002). A large literature has convincingly shown that hippocampal volume is smaller in schizophrenia patients (for review/meta-analysis, see Steen et al., 2006), as well as in their first-degree relatives (Boos et al., 2007). This is complemented by functional neuroimaging studies, which suggest that hippocampal activity is increased at baseline, but decreased during task performance (numerous studies, see PubMed results). A recent study reports that increased blood volume in the CA1 subfield of the hippocampus may predict the at-risk, or prodromal, stage of psychotic disorders (Schobel et al., 2009; see SRF related news story).

A much-discussed synthesis of hippocampal pathology in schizophrenia, which grew out of a 2007 Society for Neuroscience symposium, also gives the hippocampus a central role (Lisman et al., 2008; see also SRF related related meeting report). One hypothesis in this suite of models is that decreased hippocampal GABA signaling in schizophrenia disinhibits the outputs from the structure, leading to an overactive dopamine system (Lodge et al., 2009; see SRF related meeting report and slidecast by A.A. Grace), while another posits that the hippocampal GABA deficiency can be traced to faulty input from the basolateral amygdala (Berretta et al., 2009; see SRF related news story).

This discussion was exploratory, so we rely on our readers' comments to bring up the findings you find most compelling from your own and others’ research.

View Transcript of Live Discussion — Posted 18 January 2010

View Comments By:
Tobias Bast — Posted 2 November 2009
Stephan Heckers — Posted 3 November 2009
Inna Gaisler-Salomon — Posted 15 November 2009
Anthony Grace — Posted 16 November 2009
Melanie Foecking, David Cotter — Posted 16 November 2009
Paul Harrison — Posted 18 November 2009
Segundo Mesa-Castillo — Posted 23 November 2009

Comments on Online Discussion
Comment by:  Tobias Bast
Submitted 2 November 2009 Posted 2 November 2009

Perhaps the issue of functional differentiation along the longitudinal axis of the hippocampus may be considered?

Neuroanatomical and functional evidence (e.g., Bannerman et al., 2004; Bast, 2007; Bast and Feldon, 2003; Bast et al., 2009; Moser and Moser, 1998; Small, 2002) suggests that the septal to intermediate hippocampus, interacting with the dorsolateral band of the entorhinal cortex, plays a key role in the rapid encoding and subsequent retrieval of accurate visuospatial information; in contrast, the temporal to intermediate hippocampus is linked to behavioral control processes (including sensorimotor, emotional, motivational, and executive functions) by way of connectivity to prefrontal cortex and subcortical sites and the ascending dopamine systems.

Accordingly, the septo-temporal...  Read more

View all comments by Tobias Bast

Comment by:  Stephan Heckers, SRF Advisor
Submitted 3 November 2009 Posted 3 November 2009

This is a very good suggestion. We will review the evidence for regionally selective changes in the hippocampus in schizophrenia, including CA1 versus CA2/3 versus CA4 and anterior versus posterior hippocampus.

View all comments by Stephan Heckers

Comment by:  Inna Gaisler-Salomon
Submitted 15 November 2009 Posted 15 November 2009

As correctly pointed out by Tobias Bast, the hippocampus should no longer be viewed as a homogenous unit, and its subregions are increasingly positioning themselves as individual, yet interconnected, structures. The question that I find fascinating is, What is it about a particular subregion or tract that differentiates it from the others and makes it more vulnerable to schizophrenia-related symptoms?

A study by Schobel et al. from Scott Small’s group at Columbia, recently published in the Archives of Psychiatry (Schobel et al., 2009), was highly informative in singling out the CA1 subregion, hyperactive at baseline in both symptomatic schizophrenia patients and in prodromal subjects. The CA1 subregion is unique in its role as an integrator of contextual information, and in its ties to VTA neurons (Lisman and Otmakhova, 2001).

In Stephen Rayport’s lab at Columbia, we have recently applied the unique imaging technique used by Schobel et al. in humans to mice (  Read more

View all comments by Inna Gaisler-Salomon

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 16 November 2009 Posted 16 November 2009

Actually, these are all good points. But as with most complex systems, the parts do not operate in isolation. If one looks at both the anatomical and functional connectivity of the hippocampus, I have come to the opinion (right or wrong) that the anatomical connectivity can be interpreted on the basis of the functions. I.e., the more dorsal systems (in the rat) or more CA1-like are involved with locating one's position in space, and have the appropriate sensory inputs for such a function. But as one moves ventrally (in the rat, or anterior in the human), there are more limbic inputs, which means a translation from "where am I" to "what is the emotional salience of where I am?" This latter concept in my opinion fits in well with what we term as context.

View all comments by Anthony Grace

Comment by:  Melanie FoeckingDavid Cotter
Submitted 16 November 2009 Posted 16 November 2009

In addition to the really interesting findings in CA1, I would like to contribute recent unpublished (in preparation) findings we obtained from a proteomics investigation. We followed the hypothesis that the different subregions have distinct roles in regulation of hippocampal circuitry, and alterations within them are likely to contribute in a primary way to the clinical presentation of schizophrenia.

We aimed to characterize the differential protein expression in each of the hippocampal subregions in schizophrenia (n = 20) and bipolar disorder (n = 20) compared to control samples (n = 20). We used laser-assisted microdissection, and Difference-in-Gel-Electrophoresis to enrich for these tissues and to compare protein profiles. Samples were grouped according to the different disease/control , and we found 213 spots to be differentially expressed between disease groups in the different hippocampal subregions. Extensive statistical analysis was undertaken to correct for possible confound (pH of the brains, postmortem interval, and drug treatments).

Differential...  Read more

View all comments by Melanie Foecking
View all comments by David Cotter

Comment by:  Paul Harrison
Submitted 18 November 2009 Posted 18 November 2009

Sorry I missed the discussion, and I look forward to seeing the transcript.

The Schobel et al. study is fascinating and rightly speaks to heterogeneity within the hippocampus in schizophrenia (which likely applies also to cell populations, strata, anteorposterior gradients, etc.). Two oldish findings may be relevant to the issue.

First, we measured total (polyadenylated) mRNA content in the different hippocampal subfields in (chronic) schizophrenia and control subjects (Harrison et al., 1997). This index provides a measure of “total” gene expression and may be seen as a molecular correlate of cellular activity. Although not significant (in a small sample), there was an increase in mRNA signal in CA1 in schizophrenia, in contrast to the unchanged or decreased levels in other hippocampal and parahippocampal regions. This finding supports a relative “hypermetabolism,” and a difference, between CA1 and other subfields, in the disorder. (In passing, hyperactivity of CA1 neurons underlying paranoid schizophrenia was...  Read more

View all comments by Paul Harrison

Comment by:  Segundo Mesa-Castillo
Submitted 23 November 2009 Posted 23 November 2009

Use of new imaging technology has enabled researchers to attempt to identify regions of interest that might be related to schizophrenia. Thus far, results obtained (Shenton et al., 2001; Joyal et al., 2003; Bogerts, 1999; Mesa, 2001) indicate that the left temporal lobe is among the regions of interest; in particular, the medial structures appear to have a decrease in the volume of the amygdala, hippocampus, and parahippocampal gyrus. This suggests that exploration at the cellular level by means of other techniques such as electron microscopy could glean useful data. There is one postmortem study (Mesa, 2005) in which electron microscopic techniques were successfully implemented in studying three out of four of the regions of interest in schizophrenia research. Those areas included the primary auditory cortex, the amygdala, and the hippocampus of the left cerebral...  Read more

View all comments by Segundo Mesa-Castillo
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