What Is the Functional Significance of Hippocampal Pathology in Schizophrenia?

Abstract

The hippocampal formation (HF) is one of the brain structures most consistently altered in schizophrenia, yet the contribution of HF pathology to severe mental illness is poorly understood. We present evidence that our current ignorance is attributable to the fact that the anterior HF is heavily involved in schizophrenia but has been inadequately examined by schizophrenia investigators. We propose that the anterior HF in humans, and its counterpart in rodents (ventral HF), constrain diverse responses to psychological stimuli and that disruption of this function contributes to schizophrenia. While current data suggest that hallmark symptoms of schizophrenia most likely result from the role of the anterior HF in the integrated neurocircuit that includes the prefrontal cortex, ventral striatum, and ventral tegmental area, better characterized and phylogenetically preserved neurocircuits may be similarly affected by anterior HF pathology and account for associated findings of the disorder. We propose that focusing on the impact of ventral HF pathology on these simpler circuits and functions in rodents may provide insight into the pathophysiology of severe mental illness in humans. We review several associated findings in schizophrenia to assess the likelihood that each could be a product of this putative anterior HF dysfunction and could therefore be productively studied in rodents by probing ventral HF function.

Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

“…There is growing evidence of structural and functional anomalies of the anterior hippocampus (VH in rodents) in schizophrenia patients (Goldman and Mitchell, 2004). This includes elevated blood flow at rest and reduced activation during specific tasks (Jessen et al, 2003;Ongur et al, 2006).…”

Transient Inactivation of the Neonatal Ventral Hippocampus Impairs Attentional Set-Shifting Behavior: Reversal with an α7 Nicotinic Agonist

“…A consistent neuropathology in SZ is the subtle disruption of the anterior aspect of the hippocampal formation (Goldman and Mitchell, 2004;Harrison, 2004;Tamminga et al, 2010). While the specific, persistent chemoanatomical disruptions in the maturation of the hippocampus and its target regions following TTX on PD7 remain to be determined, they are likely to be more representative than the large, gross lesions produced by early ibotenic acid lesions of the VH.…”

Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

“…The anterior aspect of the hippocampal formation is one of the brain regions most consistently altered in SZ (Goldman and Mitchell, 2004;Harrison, 2004;Tamminga et al, 2010). Moreover, many of the cognitive deficits seen in the disorder are mediated by dysregulated interactions between the hippocampus and its principal target regions such as PFC (Henseler et al, 2010;Wolf et al, 2009), NAC (Chambers et al, 2001;Csernansky et al, 1993), and ventral tegmental area (Yang et al, 1999;Lisman et al, 2010).…”

“…In the human condition, evidence indicating hippocampal pathology in SZ suggests much more subtle alterations, with a disarray of the typical orientation of pyramidal neurons and a decline in the number of synapses (Goldman and Mitchell, 2004;Harrison, 2004). These effects have been speculated to contribute to the emergence of an imprecise (ie, poor signal-to-noise ratios) and mis-timed information flow rather than the complete absence of neuronal output (Ford et al, 2007;Tamminga et al, 2010).…”