Abstract
Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1, might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1-knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice. We found that virally induced reduction of GluA1 across multiple hippocampal subfields impaired spatial working memory. Transgene-mediated ablation of GluA1 from excitatory cells of CA2 impaired short-term memory for conspecifics and objects. Gria1 knockout in CA3 pyramidal cells caused mild impairments of object-related and spatial short-term memory, but appeared to partially increase social interaction and sustained attention and to reduce motor impulsivity. Our data suggest that reduced hippocampal GluA1 expression—as seen in some patients with schizophrenia—may be a central cause particularly for several short-term memory deficits. However, as impulse control and sustained attention actually appeared to improve with GluA1 ablation in CA3, strategies of enhancement of AMPAR signalling likely require a fine balance to be therapeutically effective across the broad symptom spectrum of schizophrenia.
Highlights
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs) containing the GluA1 subunit are essential for synaptic plasticity [1–4] and have been implicated in a variety of processes related to psychiatric diseases
We have recently identified a specific role of GluA1 in the CA2/CA3 subfields of the hippocampus, as impaired spatial short-term habituation in Gria1−/− mice could be restored by viral reintroduction of GluA1 into these circuits [33]
To dissect the role of GluA1 in distinct neuronal circuits, here we examined the behavioural consequences of Gria1 ablation in excitatory cells of either prefrontal cortex or hippocampus in a broad battery of behavioural assays, including back-translational compartments (5 min), and were exposed to a cagemate in one of the empty metal compartments while a mouse-sized piece of black foam was introduced to the other compartment
Summary
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs) containing the GluA1 subunit are essential for synaptic plasticity [1–4] and have been implicated in a variety of processes related to psychiatric diseases. Note that three other studies using ISH or Western Blot, respectively, did not find significantly altered GRIA1 expression in hippocampi from schizophrenia patients [14–16] This suggests that a hypofunction of GLUA1 may be one out of multiple molecular pathological alterations that can each impair synaptic function in the hippocampus [17, 18] and thereby causally contribute to schizophrenia. We have recently identified a specific role of GluA1 in the CA2/CA3 subfields of the hippocampus, as impaired spatial short-term habituation in Gria1−/− mice could be restored by viral reintroduction of GluA1 into these circuits [33]. It remains to be clarified, which cell types and subfields are cohorts) or 16 min (AAV-cohort) [40]. Long-term memory (the position of the familiar mouse was counterbalanced within subgroup); (iii) 10 min habituation to the novel mouse from phase 2 (with the other compartment empty) and (iv) 5 min exposure
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