Disruption and repair of synaptic plasticity and excitatory-inhibitory balance

Impaired NMDA receptor signaling is believed to contribute to schizophrenia and other psychiatric disorders. NMDA receptors are critical for neural development as well as learning, memory, and cognitive processes in adults. Thus disruption of NMDA receptor activation and synaptic transmission might lead to schizophrenia. Drugs that act as NMDA receptor antagonists (e.g., ketamine) lead to schizophrenic-like symptoms, and human genetic studies have highlighted de novo mutations in NMDA receptors and associated proteins in humans with schizophrenia. However, little is known about how NMDA receptor activation is directly involved in cognitive processes such as perception and memory. Here I will present new work in mouse models showing the connections between a gene implicated in schizophrenia (CNTNAP2), NMDA receptor activation, and control of local circuit dynamics by synaptic plasticity and regulation of excitatory-inhibitory balance in mouse sensory cortex. Methods: We performed electrophysiological experiments in brain slices and in vivo. Some behavioral experiments to examine perception and seizures were also performed. For in vitro experiments, brain slices of wild-type and Cntnap2 mutant animals were made. Synaptic transmission (strength of inhibition relative to strength of excitation) and long-term synaptic plasticity (pairing pre- and postsynaptic spikes to examine spike-timing-dependent plasticity) were assessed with whole-cell current-clamp and voltage-clamp recordings. Methods are similar to our past studies in brain slices (Froemke et al., Nature 2005; Southwell et al., Science 2010). For in vivo experiments, animals were anesthetized and head-fixed, and whole-cell recordings made in auditory or visual cortex. Sensory stimuli (pure tones/vocalizations or light flashes/ sequences, respectively) were presented to the animals; response strength and short- and long-term plasticity were measured. Methods are similar to our past studies in vivo (Froemke et al., Nature 2007; Froemke et al., Nature Neurosci 2013). Results: In Cntnap2 mutant animals, we found that: 1) NMDA receptor amplitude was decreased relative to AMPA receptor transmission, 2) long-term synaptic plasticity was impaired, 3) GABAergic inhibition was imbalanced and uncorrelated to excitation, and 4) sensory responses were unreliable and more variable than in wild-type animals. Each of these latter results (#2-4) might come as a direct consequence of impaired NMDA receptor activation (#1). However, treatment with D-serine could selectively rescue and boost NMDA receptor currents in Cntnap2 mutant mice, suggesting that glycine site modulation could improve synaptic and local circuit function in these animals. Conclusions: Many of the disruptions in Cntnap2 mutant mice (serving as a genetic model of schizophrenia) could have as a root cause reductions in current flux through NMDA receptors. However, glycine site agonists may provide a reasonable therapeutic approach for enhancing NMDA receptor function and improving cognitive processes, especially in the context of trainingbased approaches to recruit mechanisms of longterm synaptic plasticity and rebalancing inhibition with excitation