Transient hypofunction of NMDA receptors impairs spatial
discrimination in rats.
It is hypothesized that after the arrival of cortical information
conveying two similar experiences or two events close in time, the DG
uses a computational process called pattern separation to orthogonalize
(or maximize) the differences in the incoming information onto area CA3
(Yassa and Stark, 2011; Santoro, 2013). This neural mechanism is
believed to facilitate the proper storage of similar neuronal
information as independent events and prevent the overlapping of new
memories. We hypothesized that, if the DG’s integrity is compromised due
to transient hypofunction of NMDARs, the behavioral activity in which
the DG participates will also be compromised. To explore this
possibility, we evaluated MK-801-treated animals’ ability to
discriminate small changes in the spatial configuration of identical
objects maintained in a familiar environment (Santoro, 2013). The
discrimination index (DI) of this behavioral test was evaluated by
alternating the spatial configuration of identical objects in a familiar
environment (see Figure 9a for a schematic representation). A series of
spatial positions (P) was used to determine the minimal displacement
position of one object vs. another at which the animal perceived the
change in spatial position. This cognitive ability increases the demand
for spatial pattern separation activity (van Goethem et al., 2018).
In control animals, we corroborated that the DI depends on the magnitude
of displacement of one object (Figure 9b), a phenomenon previously
reported in adult animals (van Goethem et al., 2018). On the other hand,
MK-801-treated animals efficiently differentiated the change in the
spatial position of objects when displacement was maximal (DI in P5 from
control vs. MK-801: 0.41 ± 0.035 vs. 0.43 ± 0.07; n = 10 for the
control group and n = 12 for MK-801 group), and exhibited
comparable DI values in the absence of object displacement (DI in P1
from control vs. MK-801: 0.001 ± 0.021 vs. -0.01 ± 0.011). However, when
the magnitude of one object’s displacement was gradually reduced from P4
to P2, the MK-801-treated animals’ discrimination ability was reduced
(DI in P4 from control vs. MK-801: 0.38 ± 0.04 vs. 0.17 ± 0.05; DI in P3
from control vs. MK-801: 0.25 ± 0.03 vs. 0.1 ± 0.04; DI in P2 from
control vs. MK-801: 0.07 ± 0.03 vs. 0.001 ± 0.01). These differences in
DI values were significant at P3 (two-way RM ANOVA, treatment effect:
F(1, 20) = 8.225, P < 0.01; Holm–Šidák
post-hoc test, P < 0.05). The heatmaps in Figure 9c
show the spatial discrimination performance for both experimental
conditions. Although MK-801-treated animals efficiently discriminate new
object positions when the magnitude of the displacement is maximal (P5),
their mnemonic ability for spatial discrimination is reduced when the
magnitude of displacement of one object is gradually narrowed, a
condition that increases the demand of spatial pattern separation
(Figure 9d). Together, these results suggest that impaired spatial
discrimination in response to transient blockade of NMDARs may reflect
impaired pattern separation associated with psychiatric disorders such
as schizophrenia (Faghihi and Moustafa, 2015).