5. DISCUSSION
The importance of shifts in E/I balance across multiple brain regions in
the development of ASD pathology has been recognized for many years \cite{RN9,RN22,RN130}. In the hippocampus, accumulating
data now links synaptic changes to the abnormal connectivity and E/I
imbalances observed in vivo in ASD model animals. Nevertheless, it is
important to note that synaptic alterations in ASD can vary across the
different models, brain regions, and age groups under study. Regardless,
it remains essential to uncover the key mechanisms necessary for
initiation and maintenance of E/I shifts throughout the lifespan, as
well as comprehend how those shifts impact brain connectivity and
function. As the models discussed here illustrate, these E/I changes can
relate to the availability of receptors at the synapses \cite{RN131,RN31,RN9}, to changes in inhibitory circuits \cite{RN60,RN59}, or alterations in morphology \cite{RN132}; many routes to achieve a similar
functional outcome.
In understanding the development of ASD, it is crucial to consider, not
only neurons, both also the role glia play in these disorders.
Accumulating evidence of morphological, transcriptomic, and functional
changes in hippocampal astrocytes across rodent models of ASD has begun
to clarify the role they play in the shaping synaptic and cognitive
phenotypes related to the disorder. Astrocytes play an essential role in
sculpting neural circuits by coordinating synapse formation and
function, promoting neuronal survival, and guiding axonal growth in the
developing brain \cite{RN67,RN68,RN69}. Recent
studies have also demonstrated that astrocytes actively participate in
pruning dysfunctional synapses \cite{RN133,RN73} and
regulate synaptic transmission through gliotransmitter release and
removal, forming tripartite synapses in the hippocampus \cite{RN134,RN70}, thus abnormal astrocytic function
also often leads to a disruption of E/I balance. A recent study reported
the critical importance of astrocytes in ASD pathology by transplanting
astrocytes derived from ASD individuals into the hippocampus of newborn
mouse pups (P1 to P3) \cite{RN135}. The transplanted
mice exhibited distinct repetitive behaviors and memory impairment
resembling ASD, along with exaggerated astrocytic Ca2+ fluctuations in
vivo, as well as reduced long-term potentiation, neuronal network
firing, and spine density in vitro. In addition, microglia have been
well documented to be primarily responsible for synapse pruning, a
crucial process for maintaining E/I balance in the developing brain \cite{RN73,RN74}. However, once again, the nature of
these glial alterations varies depending on factors such as the specific
model, sex, and age under consideration. Nonetheless, current data make
clear that glial cells are not merely passive victims of neurocentric
pathology, but rather play an active role in the orchestration of ASD
pathology.
While shifts in E/I balance can have a plethora of consequences during
development and in the adult brain, as well as on single cell and
network activity, several in vivo measures of circuit function,
including coupling between slow and fast oscillations, modulation of
spiking by the local field potential, and the coordinated activity of
ensembles of neurons, both by theta during movement and by ripples
during rest, provide temporally sensitive and precise readouts of the
consequences of disruptions in the E/I network. While it is well
accepted, both experimentally and theoretically, that shifts in E/I
balance in either direction- a more inhibited or a more excited network-
can have disruptive effects on circuit function and cognition, this is
also true on the level of in vivo activity patterns. The most common
alterations across the models reviewed were shifts in the fine patterns
of temporal coordination of hippocampal activity. This perhaps is
unsurprising given the need for a well-tuned E/I balance to achieve
precision of spiking at the millisecond, or even tens of milliseconds,
timescale. Interestingly, in models in which single cell properties,
like place field size and average pyramidal cell firing rate, were
assessed, very few changes were noted. However, when population activity
was examined, more significant changes were observed, be the ensemble
level, with discoordination observed in the Fmr1 mice \cite{RN114}, the truncation of replay sequences in the
scn2a-/+ mice \cite{RN129} or the
ensemble level hypersynchrony observed in the Mecp2 mice \cite{RN119}.
E/I shifts in network activity may also appear in a state-dependent
fashion- both in terms of the animal’s cognitive state, i.e. memory
encoding or recall, and in terms of the physiological state of the
circuits, such as an active theta-dominated state or the large-irregular
activity and SWRs that accompany quiet wakefulness and slow wave sleep.
While a well-balanced E/I network is important for all, mechanistic
differences in the cell-types involved, the dominant excitatory inputs,
and the timescales involved may reveal specific dysfunctions in select
models. While there is clearly no singular physiological endophenotype
of ASD across the mice assessed, there are recurrent themes in the data.
A loss of oscillatory coordination and disorganization and inflexibility
of population activity, both during rest and after learning, stand out
as hallmarks of hippocampal dysfunction in ASD model mice. Moving
forward the field would benefit from the application of more standard
protocols to facilitate comparisons between the various models, as well
as the application of high-density recording and/or imaging approaches
to assess the impact of ASD risk mutations on the levels of coordination
across the population.