May 15, 2014. Weakened inhibition in the hippocampus can lead to brain overactivity similar to that found in schizophrenia, reports a study led by Holly Moore at Columbia University, New York City. Published in the Proceedings of the National Academy of Sciences on May 2, the study found that mice lacking cyclin D2 (CCND2), which encodes a protein needed to generate interneurons in the developing brain, have fewer than normal parvalbumin (PV)-containing interneurons in the hippocampus, as well as overly active neurons there and in the dopamine-containing ventral tegmental area (VTA). Restoring inhibition, in the form of interneuron precursors transplanted into the adult brain, tempered the neural hyperactivity along with attendant behavioral anomalies.
The findings lend some support to the notion that boosting inhibition in the hippocampus could restore health to the brain in schizophrenia. Though signs of compromised PV-interneurons have been found in the cortex in schizophrenia (e.g., see SRF related news report), the new study proposes that loss of PV-interneurons within the hippocampus can give rise to hyperactive brain regions associated with the disorder. This idea of “hippocampal disinhibition” was explored earlier in studies by Moore and Anthony Grace of the University of Pittsburgh, Pennsylvania, in which prenatal injections of methylazoxymethanol acetate (MAM) disturbs rat neural development in a way that gives rise to hyperactivity in both the hippocampus and in dopamine-containing neurons of the VTA (see SRF related news report). This model puts together multiple key findings in schizophrenia, including postmortem findings of decreased PV-staining, a neuropeptide that characterizes a type of interneuron, as well as brain imaging findings of increased hippocampal activity (see SRF related news report) and increased dopamine release (see SRF related news report).
The new study directly tests the notion that loss of PV-interneurons is sufficient to produce a similar state of hippocampal disinhibition. CCND2 encodes a cell cycle protein important for giving rise to new interneurons in the medial ganglionic eminence (MGE), an embryonic hotbed of neural proliferation. Though CCND2 has not been identified as a genetic contributor to schizophrenia, removing it produces a selective decrease in PV-interneurons in some areas of the cortex, including allocortical regions such as the hippocampus (Glickstein et al., 2007).
Cascade of deficits
First author Ahmed Gilani and colleagues confirmed PV-interneuron deficits in CCND2 knockout mice: The hippocampi of these mice had about one-third fewer PV-containing neurons and a concomitant decrease in the release of gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter, compared to control mice. These deficits were not found in the medial prefrontal cortex, however.
This loss of inhibition was enough to unleash activity in neurons that project out of the hippocampus. Firing rates of these neurons were twice that recorded in controls, and small animal functional magnetic resonance imaging (fMRI) also found higher than normal baseline activity in the hippocampus of CCND2 knockouts.
Behaviorally, CCND2 knockouts showed impairments in a fear conditioning paradigm that relies in part on the hippocampus. The mice also exhibited more active VTA neurons and also showed hypersensitivity to amphetamine, which, as a trigger of dopamine release, provides a readout of the overall tone of the dopamine system. Amphetamine promoted more locomotion in the CCND2 knockouts than in controls or saline-treated mice, and this could be suppressed by blockers of the D2 subtype of dopamine receptors. These results suggest that the VTA was also in overdrive in CCND2 knockouts.
To see if boosting inhibition in the hippocampus could remedy these anomalies, the researchers tried resupplying the hippocampus with new interneurons. When precursors taken from the MGE of mouse embryos were transplanted into both sides of the hippocampus, four to six months later the transplants had transformed into neurons looking much like mature interneurons, with 56 percent of them expressing PV. These transplants also reversed the various signs of hippocampal disinhibition found in CCND2 knockouts: They had lower, normal levels of hippocampus activity as measured by fMRI, they showed normal hippocampal-dependent cognition and normal levels of dopamine neuron activity, normal and responses to amphetamine.
The findings suggest that, when given a new supply of immature neurons, the adult brain can figure out how best to make use of them. Though neuron transplants may never be workable for people with schizophrenia, finding ways to boost the inhibitory powers of their interneurons in the hippocampus may prove beneficial.—Michele Solis.
Gilani AI, Chohan MO, Inan M, Schobel SA, Chaudhury NH, Paskewitz S, Chuhma N, Glickstein S, Merker RJ, Xu Q, Small SA, Anderson SA, Ross ME, Moore H.
Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci U S A. 2014 May 2. Abstract