Improving cognitive training for schizophrenia using neuroplasticity enhancers: Lessons from decades of basic and clinical research.

Mounting evidence indicates that schizophrenia is a disorder that stems from maladaptive plasticity within neural circuits and produces broad cognitive deficits leading to loss of autonomy. A large number of studies have identified abnormalities spanning many neurotransmitter systems in schizophrenia, and as a result, a variety of drugs have been developed to attempt to treat these abnormalities and enhance cognition. Unfortunately, positive results have been limited so far. This may be in part because the scope of abnormalities in the schizophrenic brain requires a treatment capable of engaging many different neurotransmitter systems. One approach to achieving this kind of treatment has been to use neuroplasticity-based computerized cognitive training programs to stimulate the formation of more adaptive circuits. Although the number of studies implementing this approach has increased exponentially in recent years, effect sizes for cognitive gains have been modest and adherence to treatment remains an important challenge in many studies, as patients are often required to train for 40 h or more. In the present paper, we argue that cognitive training protocols will benefit from the addition of cognitive enhancers to produce more robust and longer lasting targeted neuroplasticity. Indeed, recent data from animal studies have provided support for combining plasticity-enhancing drugs with tailored behavioral training paradigms to restore normal function within dysfunctioning neural circuits. The advantages and challenges of applying this approach to patients with schizophrenia will be discussed.

Synaptic activation patterns of the perirhinal-entorhinal inter-connections.

Ample neuropsychological evidence supports the role of rhinal cortices in memory. The perirhinal cortex (PRC) represents one of the main conduits for the bi-directional flow of information between the entorhinal-hippocampal network and the cortical mantle, a process essential in memory formation. However, despite anatomical evidence for a robust reciprocal connectivity between the perirhinal and entorhinal cortices, neurophysiological understanding of this circuitry is lacking. We now present the results of a series of electrophysiological experiments in rats that demonstrate robust synaptic activation patterns of the perirhinal-entorhinal inter-connections. First, using silicon multi-electrode arrays placed under visual guidance in vivo we performed current source density (CSD) analysis of lateral entorhinal cortex (LEC) responses to PRC stimulation, which demonstrated a current sink in layers II-III of the LEC with a latency consistent with monosynaptic activation. To further substantiate and extend this conclusion, we developed a PRC-LEC slice preparation where CSD analysis also revealed a current sink in superficial LEC layers in response to PRC stimulation. Importantly, intracellular recording of superficial LEC layer neurons confirmed that they receive a major monosynaptic excitatory input from the PRC. Finally, CSD analysis of the LEC to PRC projection in vivo also allowed us to document robust feedback synaptic activation of PRC neurons to deep LEC layer activation. We conclude that a clear bidirectional pattern of synaptic interactions exists between the PRC and LEC that would support a dynamic flow of information subserving memory function in the temporal lobe.