Place cells are neurons in the mammalian hippocampus that fire if the animal is in a specific place. The discovery of place cells in rats in the 1970s was awarded a Nobel Prize in 2014. Place cells have been the focus of intense study, because place cell dynamics may play a central role in mediating the important memory functions associated with the hippocampus, including spatial and episodic memory (O’Keefe, 2014).
Zaremba et al. used two-photon calcium imaging of hippocampal place cell firing in head-fixed mice performing a goal-location learning ("goal-oriented learning," GOL) task on a treadmill, to study the relationship between place cell dynamics and behavior in wild-type (WT) mice and in Df(16)A+/− mice, an animal model of human 22q11.2 deletion syndrome. This study has implications for our fundamental understanding of how place cell dynamics may mediate goal-directed learning. Moreover, 22q11.2 deletion is one of the strongest identified risk factors for schizophrenia (schizophrenia) in humans and associated with the development of schizophrenia in up to one third of all cases, although this mutation accounts for < 1% of all schizophrenia cases (Karayiorgou et al., 2010). Therefore, the changes in place cell dynamics and task performance in the Df(16)A+/− mice may have implications for our understanding of cognitive deficits, in particular memory deficits, in schizophrenia. Indeed, the authors propose that "impaired hippocampal ensemble dynamics may be a central component of cognitive memory dysfunctions emerging from the 22q11.2 DS [deletion syndrome] and schizophrenia in general." My comments will focus on two challenges in applying the findings of this study to neuro-cognitive deficits in schizophrenia.
First, it remains to be clarified how behavioral deficits on the GOL task relate to cognitive deficits in schizophrenia. The task was carefully chosen, so as to facilitate the combination of hippocampal two-photon imaging of place cell activity with behavioral testing of goal-location learning and memory. The authors suggest "that the memory deficit revealed by the GOL task is reminiscent of episodic memory deficits." However, episodic memory is the memory of unique events and assays of episodic-like memory in animal models are, therefore, based on one-trial learning (Morris, 2001). In contrast, the GOL task involves multi-trial learning across several days. In the Introduction of their paper, the authors point to "a central role of [the hippocampus] in the pathophysiology of cognitive memory deficits in schizophrenia." Their experiment using functional inhibition of the hippocampus by muscimol shows that aspects of the GOL task require the hippocampus and may, thus, be suitable to probe hippocampal dysfunction relevant to the memory deficits in schizophrenia. However, the part of the GOL task demonstrated to require the hippocampus (i.e., the initial learning of the goal location on the treadmill, as well as the expression of this memory) is actually not disrupted in Df(16)A+/− mice, and it remains to be demonstrated that those aspects of the GOL task that are impaired in Df(16)A+/− mice require hippocampal function.
The main impairment in Df(16)A+/− mice was evident following a change in the environmental context: a context change disrupted performance in the Df(16)A+/− mice, whereas it left WT mice largely unaffected (Fig. 1C, Condition II). This increased context sensitivity is not really in line with a deficit in episodic-like memory, i.e. the memory of specific events and their spatio-temporal context (Morris, 2001), which – if at all – would rather be reflected by decreased context sensitivity. It is also decreased, rather than increased, context sensitivity that has typically been associated with hippocampal dysfunction (e.g., Maren & Holt, 2000; Good et al., 2007).
An interesting possibility, raised by the authors in their Discussion, is that the increased context sensitivity reflects "a misattribution of salience to irrelevant cues." This may be relevant to the schizophrenia-related phenotype of Df(16)A+/− mice, given that impaired salience allocation/selective attention has been implicated in psychotic symptoms, and could be confirmed using dedicated assays of salience allocation/selective attention (e.g., latent inhibition or blocking paradigms) (Gray et al., 1991; Kapur, 2003; Fletch and Frith, 2009). In addition, the authors suggested that Df(16)A+/− mice were impaired in learning a new goal location on the treadmill when tested in the familiar context again. However, Df(16)A+/− mice actually learnt the new goal location at a similar rate to WT mice, it was just that they started from a lower baseline (Fig. 1C, Condition III), which may again reflect a disruption caused by the context change.
Second, it remains to be clarified how the abnormal hippocampal place cell dynamics relate to key neural biomarkers of hippocampal dysfunction in schizophrenia. More specifically, metabolic hippocampal overactivity at rest, alongside impaired hippocampal recruitment during tasks normally requiring hippocampal activation, has emerged as a key feature of schizophrenia pathophysiology; this may reflect a deficient hippocampal inhibitory GABA system, as suggested by abnormal post-mortem markers of GABA function (Heckers and Konradi, 2015; Bast et al., 2017). Interestingly, using electrophysiological recordings, the authors showed a "dysregulation of hippocampal excitability during periods of rest" in Df(16)A+/− mice, as reflected by increased rate and power of hippocampal sharp-wave ripples (SWR) activity. In addition, previous experiments suggest reduced activity of hippocampal inhibitory GABA interneurons in these mice (Drew et al., 2011). SWRs reflect synchronous burst firing of hippocampal neuron populations (Csicsvari et al., 2000) and reduced hippocampal GABA function increases hippocampal burst firing (McGarrity et al., 2017). Therefore, the increased hippocampal SWR activity in Df(16)A+/− mice points to increased hippocampal activity at rest due to impaired GABA function, reminiscent of hippocampal pathophysiology in schizophrenia (Heckers and Konradi, 2015; Bast et al., 2017).
As discussed by the authors, the abnormal place cell dynamics may be a consequence of the aberrant SWR activity, although this remains to be clarified. Another possibility that should be considered is that aspects of the abnormal place cell dynamics in Df(16)A+/− mice are a consequence (rather than a cause) of abnormal GOL task behaviour. For example, as discussed by Zaremba et al. and supported by their data from WT mice, goals and motivational factors can be reflected in place cell firing. Therefore, changed place cell dynamics in Df(16)A+/− mice during later testing stages of the GOL task (i.e., during Conditions II and III) may partly reflect that these mice were less focused on the goal locations or that they received less reward.
Overall, the neurophysiological studies by Zaremba et al. offer intriguing insights into the relation of hippocampal place cell dynamics and behavior, as well as into alterations of this relation in Df(16)A+/− mice, a genetic mouse model relevant to schizophrenia. However, the significance of these alterations for memory deficits in schizophrenia remains to be clarified. In this respect, a more detailed characterization of the behavioral phenotype of Df(16)A+/− mice, using translational assays of clinically relevant neuro-cognitive functions, would be useful.
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