Limbic Encephalitis: Potential Impact of Adaptive Autoimmune Inflammation on Neuronal Circuits of the Amygdala

Abstract

Limbic encephalitis is characterized by adaptive autoimmune inflammation of the gray matter structures of the limbic system. It has recently been identified as a major cause of temporal lobe epilepsy accompanied by progressive declarative - mainly episodic - -memory disturbance as well as a variety of rather poorly defined emotional and behavioral changes. While autoimmune inflammation of the hippocampus is likely to be responsible for declarative memory disturbance, consequences of autoimmune inflammation of the amygdala are largely unknown. The amygdala is central for the generation of adequate homoeostatic behavioral responses to emotionally significant external stimuli following processing in a variety of parallel neuronal circuits. Here, we hypothesize that adaptive cellular and humoral autoimmunity may target and modulate distinct inhibitory or excitatory neuronal networks within the amygdala, and thereby strongly impact processing of emotional stimuli and corresponding behavioral responses. This may explain some of the rather poorly understood neuropsychiatric symptoms in limbic encephalitis.

Keywords: B cells; T cells; amygdala; antibodies; autoimmunity; circuit; limbic encephalitis; neurons.

Figure 1

Putative effects of adaptive humoral and cellular autoimmunity on a simplified neuronal network. Glutamatergic principal neurons and GABAergic interneurons can be selectively targeted by neuronal antigen-specific CD8⁺ T cells based on their differential intracellular antigen expression (and presentation) [e.g., GAD65 in interneurons (blue), Hu in principal neurons (yellow)] with distinct consequences for network function and excitability. With regard to neuronal cell membrane antigens, excitatory glutamatergic synaptic transmission and plasticity can be disturbed by antibodies against NMDA and AMPA receptors, GABAergic synaptic transmission and plasticity can be disturbed by antibodies against GABA_A and GABA_B receptors. Antibodies against LGI1 and CASPR2 may interfere with both glutamatergic and GABAergic synaptic transmission and intrinsic neuronal excitability within the network, respectively.