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Transplanted GABA Precursors Prevent PCP-Induced Cognitive Deficits in Mice

21 October 2011. "Transplantation" is a word seldom heard in the context of brain disorders, much less cognitive disorders such as schizophrenia. However, a new study in the October 5 issue of the Journal of Neuroscience suggests that cognitive deficits induced by phencyclidine (PCP) administration can be prevented in mice by prior transplantation of GABAergic precursor cells into the prefrontal cortex. Because PCP and other NMDA receptor antagonists are known to produce schizophrenia-like symptoms, including cognitive deficits, in healthy individuals (Javitt and Zukin, 1991), the report by Kazunori Nakajima of Keio University in Tokyo, Japan, and Toshitaka Nabeshima of Meijo University in Nagoya, Japan, and colleagues raises the startling possibility that cell-based approaches should be considered in schizophrenia.

In both schizophrenia and NMDA hypofunction models of schizophrenia, cognitive deficits are thought to be due to alterations in cortical oscillations resulting from alterations in inhibitory interneurons such as those expressing the calcium binding protein parvalbumin (PV) or the neuropeptide somatostatin (SST) (Gonzalez-Burgos et al., 2010; Kiss et al., 2011; see also SRF Current Hypothesis). Most PV and SST cells originate from the medial ganglionic eminence (MGE; see Xu et al., 2004), and transplantation of young MGE cells into adult cortex results in their dispersion, differentiation into mainly PV and SST interneurons, and an increase in inhibition of host pyramidal cells (Wichterle et al., 1999; Alvarez-Dolado et al., 2006).

Given the purported role of PV and SST interneurons in PCP-induced cognitive deficits, first authors Daisuke Tanaka and Kayuza Toriumi examined the effect of MGE cell transplantation on PCP-induced cognitive deficits in mice. Six weeks after transplantation of MGE cells from GFP mice into the medial PFC of neonatal recipients, approximately 25 percent had survived, and of those, almost 70 percent expressed GABA. The largest fraction of cells appeared to differentiate into SST cells, with transplanted cells accounting for 11 percent of the total SST cell population. The transplanted cells appear to be functional, as indicated by a significant increase in expression of c-Fos, an immediate early gene product, in GFP-positive cells after exposure to a novel, enriched environment (a paradigm known to induce c-Fos expression).

The novel object recognition test was used to assess the cognitive function of mice 30 minutes after treatment with PCP. After a training session in which mice were familiarized to two objects, the animals were then tested in a retention session one day later in which one of the familiar objects was replaced with a novel one. Given the preference of mice to explore novelty, if a mouse can remember the familiar object, it should spend more time investigating the novel object, exhibiting exploratory preference for that object. Control mice treated with PCP demonstrated impaired exploratory preference; however, this impairment was not present in mice with prior MGE cell transplantation into the medial PFC. This effect was not present when rostromedial cortex cells were transplanted into medial PFC, or when MGE cells were transplanted into occipital cortex, indicating a necessary specificity of donor and host brain regions. Furthermore, the number of c-Fos-expressing cells was significantly higher in the medial PFC of mice with prior MGE cell transplantation than control mice. The fact that most c-Fos-positive cells were also immunoreactive for Satb2, a marker of callosal projection neurons (Alcamo et al., 2008), suggests that MGE cell transplantation modulates the activity of this population of cells.

The authors also measured paired pulse inhibition (PPI) of the acoustic startle response, a cortex-dependent measure of sensory-motor gating that is also impaired in schizophrenia (Arguello and Gogos, 2006). In this phenomenon, administration of a weaker pre-stimulus (prepulse) attenuates the startle response to a subsequent stronger stimulus (pulse). Control mice treated with PCP demonstrated reduced PPI, but mice with prior MGE cell transplantation into the medial PFC displayed normal PPI. Similar to the exploratory preference data, this effect was not present when rostromedial cortex cells were transplanted into the mPFC, or when MGE cells were transplanted into occipital cortex.

MGE cell transplantation is receiving attention as a potential treatment for other brain diseases such as epilepsy and Parkinson’s disease, and has been successfully used to ameliorate seizures (Baraban et al., 2009) as well as motor deficits (Martínez-Cerdeño et al., 2010) in rodents. Tanaka and colleagues pose the question of whether GABAergic precursor transplantion might be a treatment in schizophrenia, and while the results of these rodent studies certainly are exciting, whether this is a feasible therapeutic tool in humans undoubtedly requires volumes of further research.—Allison Curley.

Tanaka DH, Toriumi K, Kubo K, Nabeshima T, Nakajima K. GABAergic precursor transplantation into the prefrontal cortex prevents phencyclidine-induced cognitive deficits. J Neurosci. 2011 Oct 5 ; 31(40):14116-25. Abstract

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