Transient hypofunction of NMDARs during early postnatal
development impairs the frequency-dependent synaptic filtering in the
LPP – DG synapse.
A specialized feature of the LPP – DG synapse is that it operates as a
low-pass filter (Quintanilla et al., 2022). That is, while low
frequencies, such as those in the theta range, are efficiently
transferred to the DG, the high frequency patterns, i.e., the gamma
range, are greatly attenuated upon arrival to the DG. Therefore, in the
next experiment, we examined the frequency-dependent filtering property
of the LPP – DG synapse by delivering stimulation frequencies relevant
to hippocampal cognitive processing, such as the theta (5 Hz), beta (20
Hz), and low gamma (50 Hz) stimulation ranges (Engel and Fries, 2010;
Colgin, 2016).
Consistent with Quintanilla et al. (2022), in control slices, a theta
train (10 pulses at 5 Hz) induced sustained facilitation all over the
evoked synaptic responses (n = 9 slices / 6 animals; traces and
black symbols in Figures 8a1 and 8b1). The traces in Figure 8c1 also
depict the facilitated response, which contrasts the amplitude of the
first response vs. the last response (S1/S10). In contrast, the
MK-801-treated slices exhibited greater facilitation in response to 5 Hz
stimulation (n = 7 slices / 7 animals). The green symbols of the
scatter plot in Figure 8a1 show the increased facilitation of the LPP
fEPSPs in MK-801-treated slices compared to control slices (RM two-way
ANOVA, treatment effect: F(1, 14) = 7.553, P< 0.05; green traces in Figure 8b1), and the increased
facilitation in the amplitude of last response vs. first response is
depicted in the green traces in Figure 8c1.
On the other hand, in response to 20 Hz stimulation, control slices
exhibited increased facilitation on the first part of the train (second
to fifth response), which reverted in the last five responses,
generating a Gaussian-type facilitation distribution (n = 8
slices / 6 animals; symbols and black traces in Figure 8a2-c2). Contrary
to the ability to attenuate the synaptic responses, the MK-801-treated
slices exhibited greater facilitation. i.e., decreased filtering
ability. However, this phenomenon, illustrated in Figure 8a2, did not
show significant differences compared to control slices (RM two-way
ANOVA, treatment effect: F(1, 15) = 3.386, P
> 0.05; n = 8 slices / 7 animals for MK-801). The
representative traces are depicted in Figures 8b2 and 8c2.
The diminished filtering ability of the LPP – DG synapse in
MK-801-treated slices was further revealed by stimulation in the gamma
frequency range (50 Hz). Under this experimental paradigm, the control
slices exhibited enhanced facilitation in the initial portion of the
stimulation train (second to fourth response). The facilitation reverted
in the middle section and was strongly attenuated in the final section
of the train (n = 8 slices / 6 animals; symbols and black traces
in Figure 8a3-c3). Although filtering ability was present in the
MK-801-treated slices, there was still an easily identifiable decrease
under this condition compared to control slices (RM two-way ANOVA,
treatment effect: F(1, 14) = 5.285, P <
0.05, n = 8 slices / 7 animals for MK-801; green symbols in
Figure 8a3 and green traces in Figures 8b3 and 8c3). The dysregulation
in frequency-dependent filtering of LPP in MK-801-treated slices can
also be observed in the scatter plot graphs, which show the change in
amplitude between the first response and tenth response for each slice
at 5, 20, and 50 Hz train (Figure 8d-f), demonstrating reduced synaptic
filtering in MK-801-treated slices. These results show that the synaptic
property of low-pass filtering of the LPP – DG synapse is dramatically
altered in response to the transient hypofunction of NMDARs during early
postnatal development.