15 January 2009. Altered neurotransmission in the prefrontal cortex (PFC) may underlie various schizophrenia symptoms, but does the problem really originate in the cortex? Similar symptoms can be evoked in animals by damaging a deeper part of the brain early in development—the hippocampus—and this seems to impinge on behavior controlled by the PFC. Recent work shows why that might be. Reporting in the November 26 Journal of Neuroscience, researchers at Albany Medical College, New York, and the University of Pittsburgh, led by Patricio O’Donnell (now at the University of Maryland), find that while lesioning the hippocampus in young mice has no effect on the number of parvalbumin-expressing interneurons in the PFC, it does alter the ability of those cells to change their response over time to the neurotransmitter dopamine. The results indicate that the hippocampus somehow regulates maturation of PFC interneurons and hints that PFC abnormalities that emerge in human adolescence could be due to inadequate crosstalk between the hippocampus and the cortex.
Another recent study supports the idea that the hippocampus is a critical modulator of cortical activity. While these two regions of the brain are rarely on the same frequency—cortical neurotransmission oscillates in the γ frequency band (30-100 Hz), while hippocampal transmission occurs at the much lower theta band (4-8 Hz)—researchers led by Gyorgy Buzsaki at Rutgers University, Newark, New Jersey, found that the hippocampal theta oscillations entrain cortical γ rhythms. The finding raises the intriguing possibility that the hippocampus may be at least partly responsible for perturbed γ rhythms that are often found in people with, or at risk for, schizophrenia. That report was also published 26 November in the journal Neuron.
O’Donnell and colleagues’ study focused on the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia that was first introduced by Barbara Lipska, Daniel Weinberger, and colleagues at the National Institute of Mental Health, Bethesda, Maryland (see Lipska et al., 1993). Lipska and colleagues found that lesioning the ventral hippocampus in neonatal rats led to the emergence of behaviors akin to those seen when the medial prefrontal cortex was lesioned in adult animals. This led to the suggestion, now well established, that the ventral hippocampus somehow influences maturation of the prefrontal cortex.
To better understand this relationship, O’Donnell and colleagues studied PFC interneurons in rats following NVHL. Interneurons signal with the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and have a modulating effect on transmission in the cortex. It has been suggested that reduced GABAergic activity in the brain of schizophrenia patients may lead to disturbed γ oscillations, which in turn may explain changes in perception, working memory, and behavior that accompany the illness (see SRF current hypothesis and related SRF online discussion).
To see if PFC interneurons are altered by NVHL, first author Kuei Tseng (now at Rosalind Franklin University, North Chicago, Illinois) and colleagues carried out histological analysis on sections of rat brain after NVHL. The authors found no difference in expression of interneuron markers parvalbumin and GAD67 between lesioned rats and sham-operated controls. Work by coauthor David Lewis and colleagues suggests that the parvalbumin-positive subpopulation of fast-spiking interneurons is selectively perturbed in schizophrenia (see SRF interview), but these new expression data suggest that the number of parvalbumin-positive interneurons remains unchanged after the hippocampal lesion. Likewise, the basic electrophysiological properties of the interneurons appeared unchanged, since their basic firing patterns, kinetics, and amplitudes were similar to those from control rat brain.
But when Tseng and colleagues examined interneuron response to dopamine, they found a different story. Fast-spiking interneurons are stimulated by dopamine agonists specific for the D2 dopamine receptor (see Tseng et al., 2007), but in NVHL rats fast-spiking neurons failed to respond to quinpirole, a D2 agonist. “Fast-spiking interneurons have a switch in the way they are modulated by D2 agonists—during adolescence interneurons acquire an ability to be strongly recruited by dopamine—but that switch doesn’t occur in these animals,” O’Donnell told SRF.
The results suggest that it is not frank neuronal loss but a change in the properties of interneurons, namely their maturation, that underlies the phenotype of the NVHL model. It is unclear what exactly that maturation switch entails, though this is something O’Donnell plans to pursue. “My guess is that either the profile of the receptor changes or the G protein coupled to the receptor changes,” said O’Donnell. He is also intrigued by recent reports that dopamine receptors can form different heterodimers (see SRF related news story) and that the maturation of the interneurons in adolescence may reflect the emergence of a different receptor profile, which is somehow blocked by early hippocampal lesions.
Riding the waves
In the second study, Gyorgy Buzsaki and colleagues correlated theta hippocampal rhythms with γ oscillations in multiple cortical regions. First author Anton Sirota and colleagues simultaneously measured neuronal firings and oscillations in multiple sites and found that the amplitudes of neocortical neuron firings were phase-locked to theta rhythms. This phase-locking occurred in both cortical interneurons and also pyramidal neurons and occurred during REM sleep and also when animals were running on an elevated maze. Interestingly, pyramidal and interneurons, while apparently phase-entrained by theta rhythms, were not in phase with each other.
Looking more broadly at groups of neurons, the researchers found that neocortical γ rhythm bursts are modulated by the theta rhythm as well. “Essentially this is telling us that hippocampal rhythms are synchronizing high-frequency oscillations in the cortex,” said O’Donnell. “It may help us understand the integration between the hippocampus and the rest of the cortex.”
Whether the modulation of γ rhythms by hippocampal theta rhythms is abnormal in schizophrenia, or even in the NVHL model, remains to be seen. “It is possible that abnormal activity in the hippocampus is driving deficits somewhere else,” said O’Donnell.—Tom Fagan.
Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, O’Donnell P. A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J. Neurosci. 2008, November 26;28:12691-12699. Abstract
Sirota A, Montgomery S, Fujisawa S, Isomura Y, Zugaro M, Buzsaki G. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron 2008, November 26; 60:683-697. Abstract