Summary: A new study questions a long-standing idea that neurons in autistic brains suffer from too little inhibition or too much excitation. Researchers report that inhibition is not simply reduced in the brains of autism-model mice. Instead, the altered balance between excitation and inhibition appears to act as a compensatory mechanism that helps stabilize neural activity in response to genetic disruptions associated with autism spectrum disorder (ASD).
Source: UC Berkeley.
New research in four autism mouse models challenges the commonly held view of what goes wrong in brain circuits to produce autism-related symptoms.
For years, a dominant hypothesis has held that autism involves an imbalance between neuronal excitation and inhibition: specifically, that reduced inhibition or excessive excitation produces hyperexcitability and increased neuronal spiking. That excess spiking has been proposed to create neural “noise” that interferes with normal processing and contributes to the core symptoms of autism in people — difficulties with social interaction, language and communication, repetitive behaviors, and heightened sensitivity to sensory input.
Because of this hypothesis, several research efforts aim to increase overall inhibition in the brain—through drugs or genetic approaches—with the expectation that restoring excitation-inhibition balance might relieve symptoms.
In a new paper, neuroscientists at the University of California, Berkeley report results that complicate that story. While they confirm that inhibition is reduced in several autism mouse models, they also find excitation is reduced alongside it (though to a lesser degree), and the coordinated changes leave neuronal spiking largely unchanged. Rather than driving hyperexcitability, the altered excitation-inhibition (E-I) ratio may reflect a homeostatic compensation that stabilizes circuit activity.
“Many groups are searching for ways to increase inhibition in the brain, either through drugs or through gene therapy, on the assumption that increasing inhibition will restore the brain back to normal,” said study leader Daniel Feldman, professor of molecular and cell biology and member of the Helen Wills Neuroscience Institute at UC Berkeley. “Our results suggest that reduced inhibition could be a compensatory adjustment by the brain, or might be unrelated to core behavioral symptoms. Intervening to increase inhibition could therefore be ineffective—or even counterproductive.”
Feldman and colleagues argue that these findings should prompt researchers to revisit the underlying causes of altered inhibition and excitation and to investigate what roles these changes actually play in circuit function and behavior.
The UC Berkeley team published their findings in the journal Neuron on January 21.
Using mouse models to probe mechanisms
“Autism is a complex puzzle,” Feldman said. “Genetic studies over the past decade show that at least half of autism risk traces to genetics, but the risk is spread across many different genes. How can different genetic mutations produce similar features across the autism spectrum?”
Mouse models have become a useful tool for addressing that question. Each mouse strain used in this study carries a single genetic mutation that corresponds to one found in some people with autism, and the animals display behavioral traits analogous to human symptoms, such as impaired social interactions and repetitive behaviors.
To test whether a common E-I imbalance drives circuit dysfunction across distinct genetic forms of autism, the researchers examined synaptic inputs and neuron firing in four well-validated mouse models. In each model they measured feedforward excitation and inhibition in layer 2/3 of somatosensory cortex and analyzed how these synaptic changes affected membrane depolarization and spiking.
Across all four models, feedforward inhibition was consistently reduced. Feedforward excitation was also reduced but to a lesser extent, producing an increase in the excitation-inhibition (E-I) conductance ratio. Under the traditional hypothesis, an elevated E-I ratio would be expected to increase neuronal firing. Instead, the researchers found that neurons maintained normal spiking rates.
Computational modeling and electrophysiological measurements showed that reductions in excitation and inhibition were precisely coordinated so that synaptic depolarization near spike threshold remained stable. In other words, the E and I changes offset each other, preserving overall excitability despite an increased E-I ratio.
Feldman interprets these results as evidence of a homeostatic or compensatory response: neurons adjust their synaptic inputs to stabilize firing in the face of genetic perturbations. However, this compensation may carry costs. For example, lowering inhibition could reduce the precision of how neurons encode sensory input, degrading the fidelity of neural representations without changing overall spike count.
“The excitation-inhibition changes may successfully preserve average firing rates, but a side effect could be impaired information coding,” Feldman said. “So even if spike number is unchanged, the timing or selectivity of spikes might be degraded, which could contribute to sensory and cognitive symptoms.”
The team is continuing to investigate how reduced inhibition might affect other aspects of circuit function that could explain sensory hypersensitivity and behavioral features observed in these mice.
The study was led by Miller Postdoctoral Fellow Michelle Antoine, graduate student Tomer Langberg and former postdoc Philipp Schnepel of UC Berkeley, who contributed equally. Funding came from the Simons Foundation, the National Institutes of Health (R01 NS105333), the Miller Institute for Basic Research at UC Berkeley, and the Ford Foundation.
Source: Robert Sanders, UC Berkeley.
Publisher: Neuroscience News.
Image Source: Neuroscience News image in the public domain.
Original Research: “Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models,” by Michelle W. Antoine, Tomer Langberg, Philipp Schnepel, and Daniel E. Feldman, published in Neuron on January 21, 2019. doi: 10.1016/j.neuron.2018.12.026
Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models
Distinct genetic forms of autism are hypothesized to share a common increase in the excitation-inhibition (E-I) ratio in cerebral cortex, producing hyperexcitability and excess spiking. The authors provide a systematic test of this hypothesis across four mouse models (Fmr1 -/y, Cntnap2 −/−, 16p11.2 del/+, Tsc2 +/−), focusing on somatosensory cortex. All mutants showed reduced feedforward inhibition in layer 2/3 along with a more modest, variable reduction in feedforward excitation, yielding a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that the changes in excitatory and inhibitory conductances were quantitatively matched in each mutant to stabilize synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite reduced inhibition. Thus, elevated E-I ratio appears to be a shared circuit phenotype that reflects homeostatic stabilization of synaptic drive rather than causing network hyperexcitability in these autism models.