All-optical synaptic electrophysiology probes mechanism of ketamine-induced disinhibition

Abstract

Optical assays of synaptic strength would greatly facilitate studies of neuronal transmission and its dysregulation in disease. Here we introduce a genetic toolbox for all-optical interrogation of synaptic electrophysiology (‘synOptopatch’) via mutually exclusive expression of a channelrhodopsin actuator and an archaerhodopsin-derived voltage indicator. Optically induced activity in the channelrhodopsin-expressing neurons generated excitatory and inhibitory post-synaptic potentials which were optically resolved in the reporter-expressing neurons. We further developed a yellow spine-targeted Ca 2+ indicator to localize optogenetically triggered synaptic inputs. We demonstrated synOptopatch recordings in cultured rodent neurons and in acute rodent brain slice. In synOptopatch measurements of primary rodent cultures, acute ketamine administration suppressed disynaptic inhibitory feedbacks, mimicking the effect of this drug on network function in both rodents and humans. We localized this action of ketamine to excitatory synapses onto interneurons. These results establish an in vitro all-optical model of disynaptic disinhibition, a synaptic defect hypothesized in schizophrenia-associated psychosis.

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

“…Although in principle the disinhibition hypothesis is general and need not be tied to particular GABAergic neuron subtypes, so far empirical studies of NMDAR hypofunction have focused on fast-spiking cells for technical reasons. For example, recordings of inhibitory postsynaptic currents have provided clear evidence for disinhibition 32,33 , but the method cannot distinguish the cell types that provide the GABAergic inputs, and an electrode placed at the soma tends to favor the detection of perisomatic inputs. In vivo electrophysiology has also supported disinhibition by showing reduced activity for fast-spiking cells 11 , but SST interneurons are likely not examined in this earlier study because their spike waveforms have overlapping features with excitatory neurons and thus cannot be easily isolated 16 .…”

Aberrant Auditory Steady-State Response of Awake Mice After Single Application of the NMDA Receptor Antagonist MK-801 Into the Medial Geniculate Body

“…It has been established that synaptic interactions between GABAergic interneurons and pyramidal neurons determine the excitation/inhibition balance in neural circuit functioning and contribute to the generation of gamma oscillations ( Cardin et al, 2009 ; Sohal et al, 2009 ). There is also evidence that NMDARs contribute more to the excitatory postsynaptic currents in GABAergic interneurons than in pyramidal neurons ( Jones et al, 1993 ), and ketamine/MK-801 preferentially blocks NMDARs in GABAergic interneurons ( Homayoun et al, 2007 ; Suryavanshi et al, 2014 ; Fan et al, 2018 ). Thus, it is important to further examine the hypothesis that GABAergic interneurons are particularly affected by NMDAr hypofunction in SZ ( Cohen et al, 2015 ).…”

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

“…Although in principle the disinhibition hypothesis is general and need not be tied to particular GABAergic neuron subtypes, so far empirical studies of NMDAR hypofunction have focused on fast-spiking cells for technical reasons. For example, recordings of inhibitory postsynaptic currents have provided clear evidence for disinhibition 30,31 , but the method cannot distinguish the cell types that provide the GABAergic inputs, and somatic electrodes tend to favor the detection of perisomatic inputs. In vivo electrophysiology has also supported disinhibition by showing reduced activity for fast-spiking cells 12 , but again SST interneurons are likely not examined in this earlier study because their spike waveforms have overlapping features with excitatory neurons and thus cannot be easily isolated 17 .…”