4. Hippocampal neural circuit activity in ASD model mice
One of the benefits of modeling genetic disorders in the mouse is the
ability to understand at a circuit and systems level how changes in
behavior are related to changes in the well-understood physiology of the
hippocampal formation \cite{RN94,RN23}. The last fifty
years of research has given us a rich template of physiological
signatures or correlates of mnemonic processing in the hippocampus,
including the formation and spatial coding of place cells \cite{RN95,RN13}, the temporally organized activity of
ensembles of place cells, both during movement and sleep, as well as the
oscillatory patterns which dominate the hippocampal local field
potential, theta (4-12Hz) gamma (30-100Hz) and sharp wave ripples (SWR;
120-180Hz) \cite{RN97,RN96,RN98,RN99}, which can shed
light on how information flow and processing are altered in a dynamic
manner (Figure 2). Although these physiological measures are complex,
they can serve as indicators of how changes in the balance between
excitation and inhibition are manifest on the population level during
specific behavioral or memory states.
Theta is most prominent oscillation in the hippocampus during locomotion
and attention and has been tightly linked to memory function, with
manipulations that decrease theta power linked to encoding deficits \cite{RN102,RN13,RN100,RN101,RN103}. Gamma oscillations are
modulated by movement velocity, sensory processing, attention, and
cognition and memory and in CA1, have been used as a proxy for the
influence of CA3 (low gamma 30-60 Hz) and entorhinal cortical (high
gamma, 60-100 Hz) inputs on circuit function \cite{RN104}. Moreover, the timing and amplitude of
these distinct gamma bands can be modulated by the slower theta
oscillation, a phenomenon termed cross-frequency coupling, thought to be
important for the temporal organization of circuit activity \cite{RN97,RN94,RN105,RN106}.
Finally, SWRs, triggered by input from CA3 and/or CA2 \cite{RN99,RN107,RN108} create short periods
(~100-200 msec) of precise temporally organized neuronal
spiking during slow-wave sleep and quiet wakefulness and have been
implicated in memory consolidation, storage and recall \cite{RN99}. All these oscillations require not just
external inputs to the CA1 region, but also precise interaction in local
microcircuits containing both excitatory and inhibitory neurons \cite{RN99}. Thus, understanding how genetic models of
ASD impact these rhythms and the temporal and sequential coordination of
spiking in the structure they support is an important bridge between
behavioral phenotypes and shifts in E/I balance on the level of circuits
and synapses.
Both mouse \cite{RN40,RN109} and rat \cite{RN110,RN111} models of FXS have been generated and
subject to in vivo electrophysiological analysis. Two studies recorded
from the CA1 region of Fmr1-/- mice performing an
active place avoidance task \cite{RN113,RN112} and
observed changes in the temporal and spatial coordination of hippocampal
oscillations in a cognitive state dependent manner, with alterations in
the patterns of coupling between the theta and slow gamma rhythms, as
well as an inflexibility of the spatial representations in the
Fmr1-/+ mice. A third study from the same lab \cite{RN114} recorded CA1 neuronal activity and local
field potential in Fmr1-KO mice in a fixed context and found that while
place fields were relatively intact, on the network level pyramidal
cells were less modulated by ongoing theta and gamma oscillations and
place cells with overlapping fields showed a decrease in positively
correlate firing, forming weaker cell assemblies. Another 2018 study
from Arabab et al using the same model \cite{RN115}reported increases in theta power and local gamma coherence on the LFP
level. On the network level they observed the pairs of interneurons in
CA1, as well as interneuron-pyramidal cell pairs, showed significant
decreases in spike count correlation, indicating a reduction in the
correlated variance of these cell assemblies, and hypersynchrony between
inhibitory neuron firing and the theta and gamma oscillations. A third
group published a 2018 study recording in the CA1 region of Fmr1-KO mice \cite{RN116} finding a significant decrease in the
frequency of REM sleep, increased firing of pyramidal cells during both
wakefulness and rest, an increase in low gamma power and alterations in
SWRs, with longer and slower oscillations coupled with a decrease in
pyramidal cell firing across the events. While there are some
disparities between these results, which could be related to the tasks
and contexts employed for recording, there is consistent findings of
dysregulation of oscillatory coupling of neurons with the local field
potential and changes in network coordination.
More recently \cite{RN117} Asiminas et al reported the
first in vivo recordings from the hippocampus of a rat model of FXS.
They observed while place fields in a novel environment were similar
between control and Fmr1-KO rats, the FXS-model animals failed to show
experience-dependent improvements in spatial coding when returned to the
context the following day. Further, consistent with results from mice,
they observed a decrease in the modulation of pyramidal cell firing by
the slow gamma oscillation and significant shifts in the preferred
firing phase of pyramidal cells to both theta and slow gamma.
Hippocampal activity in the Mecp2-/+ mice has also
been carefully studied at the single neuron and network levels. Lu et al \cite{RN50} used both 2-photon calcium imaging and in
vivo electrophysiology to establish that while CA1 pyramidal cells in
the KO mice are overall less active, they showed a significant increase
in synchronous activity, which interestingly could be rescued by deep
brain stimulation of the fornix. A second study employing high-density
tetrode recording in the CA1 region \cite{RN118} found
that, like what was reported in the Fmr1-KO rats \cite{RN117}, place fields in the KO mice failed to
show experience-dependent improvements in the spatial coding.
Interestingly, the authors also observed the hypersynchronous activity
in these mice extended to the SWR events, perhaps occluding
learning-dependent consolidation mechanisms necessary for place field
refinement. Finally, a recent study \cite{RN119} employed 1-photon calcium imaging in the CA1 of
Mecp2-/+ mice subject to contextual fear conditioning
and observed that during memory recall the active CA1 neuronal ensembles
were larger and more correlated, changes the authors attributed to a
specific deficit in the function of the OLM class of CA1 interneurons.
A recent study examined the impact of the deletion of NGL3 on
hippocampal physiology \cite{RN120}, focusing on the
dorsal CA2 and CA3 regions of the circuit, as they have been implicated
in social memory \cite{RN121,RN122}. These mice, which
have an impairment in social behavior, demonstrated CA2 specific
alterations in the entrainment of pyramidal cell spiking by slow
oscillations, as well as decrease in gamma power in both the CA2 and CA3
regions. Ex vivo recordings found a shift in the E/I balance towards
excitation, with CA2 pyramidal cells in the KO mice showing an increase
in spontaneous excitatory input with a concomitant decrease in
spontaneous inhibitory input, suggesting this shift of the local network
excitation could connect the impairments in oscillatory activity and
temporal coordination of spiking to deficits in social behavior.
Cntnap2 KO mice capture ASD-like behavioral phenotypes, including social
impairments, reduced vocalization repetitive behaviors and impaired
cognition \cite{RN123}, and in the CA1 region have an
E/I balance shifted towards excitation, with reduced perisomatic
inhibition of pyramidal cells \cite{RN60,RN59}. In vivo
hippocampal recordings in behaving mice revealed that during movement
there was an overall decrease in theta power, as well as impaired
phase-amplitude coupling between fast gamma, thought to reflect inputs
from the entorhinal cortex (EC), and theta oscillations in the KO mice.
During rest, the occurrence of ripples decreased, as did the amplitude
of the oscillations themselves, with no change in the size of the sharp
wave, suggesting CA3 input was unchanged. This is consistent with the
observation of a decrease in PV density and a decrease in inhibitory
input to pyramidal cells, suggesting this is a result of the shift in
the local E/I balance that dampens the ability of the circuit to
generate oscillations capable of entraining pyramidal cell activity \cite{RN59}.
Three studies have examined the impact of the loss of function of Shank3
on hippocampal in vivo physiology, making it one of the best
characterized models in terms of circuit function. Dhamne et al. \cite{RN124} conducted long-term EEG recordings in
control and Shank3B-/- mice, both under baseline
conditions and following chemical induction of seizure. Interestingly,
these mutants were resistant to PTZ induced seizure, suggesting an E/I
balance shifted to increased inhibition and/or reduced excitation,
consistent with ex vivo recording data \cite{RN124}.
Further, under baseline conditions Shank3B-/- mice
demonstrated increased power in the gamma band. Cope et al. \cite{RN125} recorded from the ventral CA1 region of
the same Shank3B-/- mice during social behavior and
observed no change in theta or gamma power in the mutants but did
observe that chemogenetic activation of the CA2 region increased CA1
theta power specifically in the KO mice and led to a concomitant rescue
of social behavioral deficits. Interestingly, a recent study from Tao et
al. \cite{RN126} conducted a similar study, recording
in vCA1 of control and Shank3-/- mice during a social
discrimination task and found a decrease in the fraction of cells
encoding social information during the task, as well as a decrease in
the power of SWRs and a decrease in the correlation between cell
sequences observed during behavior and SWRs. These results suggested an
impairment in the reactivation of social sequences in these animals.
Mechanistically, the phase locking of interneurons to the SWR
oscillation was impaired in the mutants relative to controls, although
there were no differences in the entrainment of PC firing, suggesting
the shift in the activity of the inhibitory neurons may underlie the
impairments in the re-expression of sequential activity.
In vivo hippocampal activity has also been examined in SHANK2 deficient
mice. Sato et al. \cite{RN127} employed longitudinal
2-photon calcium imaging of CA1 pyramidal cell activity in head-fixed
mice performing a virtual reality-based goal localization task. While
the pyramidal cells in control mice stably overrepresented both the
locations of landmarks and rewards following learning, Shank2 mutant
mice, engineered to mimic a human ASD-linked microdeletion, demonstrated
overrepresentation of the reward sites, but not at the location of
salient landmarks.
Turning to genes that impact neuronal excitability, mice that are
haploinsufficent for Scn1a (SCN1a+/-) exhibit impaired
social and spatial cognition and stereotypic behaviors and in vitro
recordings in CA1 revealed a profound shift in the E/I balance, with
reduced spontaneous inhibitory currents and enhanced spontaneous
excitatory currents \cite{RN61}. Recently, in vivo
recording was performed in the hippocampus of rats with injected with a
short-hairpin virus to knockdown expression of the Nav1.1 channel \cite{RN128}. They observed a specific decrease in the
firing rate of inhibitory neurons, consistent with the ex-vivo data, and
a shift in the E/I balance towards increased excitation. On the level of
oscillations this resulted in weaker phase-amplitude coupling between
theta and gamma and impairments in the theta-modulated spiking of PCs.
There was a shift of the preferred phase to the descending phase of
theta and significantly weaker theta phase precession. Further, on the
sequence level, the relationship between the spiking of pairs of place
cells with nearby place fields, typically observed in normal rats, was
impaired, with a breakdown of the expected relationship between distance
of the fields and phase offset.
Finally, recordings in the CA1 region of freely behaving
SCN2a+/- mice found no changes in theta or gamma
oscillations during exploration, nor in the firing or spatial coding of
the pyramidal cells. However, during SWRs there was a significant
reduction in the reactivation of cell assemblies, and on the level of
sequences, the replay of behavioral place-cell sequences was
significantly shorter, attributed to shift in the E/I balance towards
increased inhibition \cite{RN129}. Although the loss of
a single copy of Nav1.1 and Nav1.2 led to distinct physiological
phenotypes, they both resulted in a decrease in the ability of the
hippocampus to accurately represent longer trajectories through space,
consistent with dysfunction in the local CA1 circuits.