ReviewGABAergic mechanisms of hippocampal hyperactivity in schizophrenia
Section snippets
Evolution of the hippocampal hyperactivity model
Even before any studies of the hippocampus, several authors proposed models of hippocampal hyperactivity in schizophrenia (Krieckhaus et al., 1992, Venables, 1992). These authors hypothesized that deficits seen in patients with schizophrenia (e.g., latent inhibition and negative priming) are caused by hippocampal hyperactivity, but did not provide any experimental data. This changed with Peter Liddle's 1992 study of patterns of cerebral blood flow in schizophrenia and Francine Benes' 1998 study
Excitation–inhibition balance in the hippocampus
The hyperactivity model of schizophrenia states that the excitation–inhibition (E/I) balance is abnormal in psychosis (Uhlhaas, 2013). This has been proposed for several brain areas, including the hippocampus. Here we will briefly review the E/I balance in the human hippocampus.
Abnormal hippocampal activity in schizophrenia
Studies of regional cerebral glucose metabolic rates (rCMRglc), regional cerebral blood flow (rCBF) and blood oxygen level-dependent (BOLD) signal demonstrate abnormal hippocampal activity in schizophrenia (Buchsbaum et al., 1992, Nordahl et al., 1996, Tamminga et al., 1992) (Friston et al., 1992, Kawasaki et al., 1996, Kawasaki et al., 1992, Lahti et al., 2003, Liddle et al., 1992, Malaspina et al., 2004, Medoff et al., 2001). Changes of hippocampal metabolism and blood flow are associated
Reduced number of interneuron populations
While the total number of hippocampal neurons is normal in schizophrenia (Heckers et al., 1991, Konradi et al., 2011a, Schmitt et al., 2009, Walker et al., 2002), several studies have revealed selective abnormalities of interneurons. Benes et al. provided evidence for a decreased density of non-pyramidal cells in the hippocampus in schizophrenia and psychotic bipolar disorder (Benes et al., 1998). A subsequent study in these patient populations revealed decreased mRNA levels of glutamic acid
Animal models of hippocampal hyperactivity
Several animal studies linked an impairment of parvalbumin-positive interneurons to abnormal hippocampal activity and schizophrenia-like behavior. Inhibition of NMDA-receptors in the hippocampus (especially in sector CA1) decreases activity of parvalbumin-positive interneurons, which in turn leads to a disinhibition of hippocampal pyramidal cells (Behrens et al., 2007, Bickel and Javitt, 2009, Greene, 2001, Kinney et al., 2006, Lisman et al., 2008). Furthermore, administration of
Hippocampal hyperactivity develops in stages
Schobel et al. pioneered the longitudinal study of hippocampal activity in schizophrenia (Schobel et al., 2013). They followed subjects at risk for schizophrenia for 2 years and measured changes in CBV and hippocampal structure. They reported that subjects with higher CA1 CBV values showed greater hippocampal volume reduction after 2 years (Schobel et al., 2013). We propose that hippocampal hyperactivity in schizophrenia develops in stages.
Accounting for heterogeneity
Brain changes, even robust findings such as smaller hippocampal volume, are not diagnostic for schizophrenia (Heckers et al., 2013). Several scenarios can account for this heterogeneity and need to be considered as we test the model of hippocampal hyperactivity in psychosis.
Patients who carry a significant burden of risk for the development of an abnormal hippocampus might show cognitive deficits and smaller hippocampal volume already at baseline and in the at-risk state. This includes patients
Implications for treatment
Treating the hyperactive hippocampus is a possible intervention strategy in the early stages of psychosis. This approach shows great promise in the early stages of Alzheimer's disease. In animals that overexpress human amyloid precursor protein, the hippocampus shows spontaneous epileptiform discharges, primarily during reduced gamma oscillatory activity, which was linked to parvalbumin cell dysfunction (Verret et al., 2012). The anticonvulsant levetiracetam suppressed the abnormal spiking
Summary
We propose that the neuroimaging (BOLD, CBV, and rCBF) finding of hippocampal hyperactivity in schizophrenia is due to cellular and molecular changes of hippocampal interneurons, primarily somatostatin-positive and parvalbumin-positive interneurons. We do not dispute the important role of other mechanisms (e.g., NMDA-receptor hypofunction, alpha7 nicotinergic receptor dysfunction), but for the purpose of this review we have focused on GABAergic mechanisms. We suggest that hippocampal
Role of the funding source
This work was supported by the National Institute of Mental Health (grant R01 MH070560 to SH).
Contributors
SH and CK wrote, edited and approved the manuscript.
Conflict of interest
Dr. Heckers has received funding from the National Institute of Mental Health.
Acknowledgment
SH is supported by the National Institute of Mental Health (grant R01 MH70560).
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