CKAMP44 modulates integration of visual inputs in the lateral geniculate nucleus

Abstract

Relay neurons in the dorsal lateral geniculate nucleus (dLGN) receive excitatory inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses are characterized by a prominent short-term depression of AMPA receptor (AMPAR)-mediated currents, but the underlying mechanisms and its function for visual integration are not known. Here we identify CKAMP44 as a crucial auxiliary subunit of AMPARs in dLGN relay neurons, where it increases AMPAR-mediated current amplitudes and modulates gating of AMPARs. Importantly, CKAMP44 is responsible for the distinctive short-term depression in retinogeniculate synapses by reducing the rate of recovery from desensitization of AMPARs. Genetic deletion of CKAMP44 strongly reduces synaptic short-term depression, which leads to increased spike probability of relay neurons when activated with high-frequency inputs from retinogeniculate synapses. Finally, in vivo recordings reveal augmented ON- and OFF-responses of dLGN neurons in CKAMP44 knockout (CKAMP44−/−) mice, demonstrating the importance of CKAMP44 for modulating synaptic short-term depression and visual input integration.

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis

“…For instance, synaptic strength may be increased and short-term plasticity affected with an increased number of CKAMP44-bound AMPA receptors 34,35 . Importantly, based on previous findings on the function of CKAMP44 50 , a possible consequence may be a more pronounced short-term depression, which could be a homeostatic mechanism to protect neurons in hyperactive network states. In addition, GSG1L decreases conductance of AMPARs 51 .…”

AMPA Receptor Auxiliary Subunit GSG1L Suppresses Short-Term Facilitation in Corticothalamic Synapses and Determines Seizure Susceptibility

“…Similar to GSG1L, CKAMP44 slows recovery from desensitization, modulates short-term plasticity, and is expressed in AD/AV ( Figure S4E ) ( von Engelhardt et al, 2010 ; Chen et al, 2018 ). We found that M-T synapses in AD/AV undergo pronounced STD ( Figures 1J – 1L and S2A – S2C ), which is highly sensitive to CTZ (data not shown).…”

“…AMPAR desensitization is critical for normal brain function ( Christie et al, 2010 ). CKAMP44 regulates AMPAR desensitization and contributes to the underlying mechanism of STD in retinogeniculate synapses ( Chen et al, 2018 , 2000 ; Kielland and Heggelund, 2002 ; Budisantoso et al, 2012 ). The glomerular structure of the retinogeniculate synapse has large terminals and closely spaced release sites ( Rafols and Valverde, 1973 ).…”

“…In these synapses, AMPAR desensitization is predicted to not contribute to short-term plasticity, such as observed in the ventrobasal nucleus ( Sun and Beierlein, 2011 ). CKAMP44 plays no role in short-term plasticity at corticogeniculate synapses in the LGN ( Chen et al, 2018 ). In contrast, we found that AMPAR desensitization substantially contributes to short-term plasticity at C-T synapses in AD/AV.…”

AMPA Receptor Auxiliary Proteins of the CKAMP Family

“…AMPA receptor current amplitudes are reduced in dentate gyrus granule cells and lateral geniculate nucleus relay neurons of CKAMP44-deficient mice. Overexpression of CKAMP44 has the opposite effect [16,24]. How CKAMP44 promotes the surface expression of AMPA receptors is unclear.…”