Biology subjects

Messier, J. E.

Publications and source records attributed to Messier, J. E..

3 recordsLinked to original sources

bioRxiv2022

Cell-type specific deletions of Neuroligin 2 reveal a vital role of synaptic excitation-inhibition balance

Synaptic excitation (E) and inhibition (I) stay relatively proportional to each other over different spatiotemporal scales, orchestrating neuronal activity in the brain. This proportionality, referred to as E-I balance, is thought to be critical for neuronal functions because its disruption was observed in many neurological disorders. However, the causal evidence demonstrating its significance is scarce. Here we show that deleting Neuroligin-2 (Nlgn2), a postsynaptic adhesion molecule at inhibitory synapses, from mouse glutamatergic or GABAergic neurons reduces inhibition cell-autonomously without affecting excitation, thereby disrupting E-I balance and causing lethality. In contrast, deleting Nlgn2 constitutively or simultaneously from both glutamatergic and GABAergic neurons results in viable mice. A neural network model shows that reducing inhibition in either neuronal type is detrimental to network activity, but in both types partially re-establishes E-I balance and activity. Together, our results provide evidence for an essential role of E-I balance in brain functions and organism survival.

neuroscience↗

bioRxiv2019

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, but the underlying pathogeneses are poorly understood. Syntaxin-binding protein 1 (STXBP1) is an essential component of the neurotransmitter release machinery. Its de novo heterozygous mutations are among the most frequent causes of neurodevelopmental disorders including intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 encephalopathy, affect a broad spectrum of neurological and neuropsychiatric features common among neurodevelopmental disorders. To gain insight into STXBP1 encephalopathy pathogenesis, we generated new Stxbp1 null alleles in mice and found that Stxbp1 haploinsufficiency impaired cognitive, psychiatric, and motor functions and caused cortical hyperexcitability and seizures. Surprisingly, Stxbp1 haploinsufficiency reduced neurotransmission from cortical parvalbumin- and somatostatin-expressing GABAergic interneurons by differentially decreasing the synaptic strength and connectivity, respectively. These results demonstrate that Stxbp1 haploinsufficient mice recapitulate key features of STXBP1 encephalopathy and indicate that inhibitory dysfunction is likely a key contributor to the disease pathogenesis.

neuroscience↗

bioRxiv2018

Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon

Light-gated chloride channels are emerging as promising optogenetic tools for inhibition of neural activity. However, their effects depend on the transmembrane chloride electrochemical gradient and may be complex due to the heterogeneity of this gradient in different developmental stages, neuronal types, and subcellular compartments. Here we characterized a light-gated chloride channel, GtACR2, in mouse cortical neurons. We found that GtACR2 activation inhibited the soma, but unexpectedly depolarized the presynaptic terminals resulting in neurotransmitter release. Other light-gated chloride channels had similar effects. Reducing the chloride concentrations in the axon and presynaptic terminals diminished the GtACR2-induced neurotransmitter release, indicating an excitatory effect of chloride channels in these compartments. A novel hybrid somatodendritic targeting motif reduced the GtACR2-induced neurotransmitter release while enhancing the somatic photocurrents. Our results highlight the necessity of precisely determining the effects of light-gated chloride channels under specific experimental conditions and provide a much-improved light-gated chloride channel for optogenetic inhibition.

neuroscience↗