Chemogenetic rectification of the inhibitory tone onto hippocampal neurons reverts autistic-like traits and normalizes local expression of estrogen receptors in the Ambra1+/- mouse model of female autism.

Female, but not male, mice with haploinsufficiency for the proautophagic Ambra1 gene show an autistic-like phenotype associated with hippocampal circuits dysfunctions which include loss of parvalbuminergic interneurons (PV-IN), decrease in the inhibition/excitation ratio, and abundance of immature dendritic spines on CA1 pyramidal neurons. Given the paucity of data relating to female autism, we exploit the Ambra1+/- female model to investigate whether rectifying the inhibitory input onto hippocampal principal neurons (PN) rescues their ASD-like phenotype at both the systems and circuits level. Moreover, being the autistic phenotype exclusively observed in the female mice, we control the effect of the mutation and treatment on hippocampal expression of estrogen receptors (ER). Here we show that excitatory DREADDs injected in PV_Cre Ambra1+/- females augment the inhibitory input onto CA1 principal neurons (PN), rescue their social and attentional impairments, and normalize dendritic spine abnormalities and ER expression in the hippocampus. By providing the first evidence that hippocampal excitability jointly controls autistic-like traits and ER in a model of female autism, our findings identify an autophagy deficiency-related mechanism of hippocampal neural and hormonal dysregulation which opens novel perspectives for treatments specifically designed for autistic females.

Hippocampal epileptogenesis in autoimmune encephalitis.

OBJECTIVE: Autoantibody-mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential. METHODS: We compared the effects of CSF containing leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid receptor B (GABAB R) antibodies on ex vivo electrophysiological parameters after stereotactic hippocampal inoculation into mice. Whole-cell patch-clamp and extracellular recordings from CA1 pyramidal neurons and CA3-CA1 field recordings in ex vivo murine brain slices were used to study neuronal function. RESULTS: By comparison to control CSF, AE CSFs increased the probability of glutamate release from CA3 neurons. In addition, LGI1- and CASPR2 antibodies containing CSFs induced epileptiform activity at a population level following Schaffer collateral stimulation. CASPR2 antibody containing CSF was also associated with higher spontaneous firing of CA1 pyramidal neurons. On the contrary, GABAB R antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials. INTERPRETATION: Using patient CSF, we have demonstrated that the AE-associated antibodies against LGI1 and CASPR2 are able to increase hippocampal CA1 neuron excitability, facilitating epileptiform activity. These findings provide in vivo pathogenic insights into neuronal dysfunction in these conditions.