Cross-frequency coupling supports the organization of brain rhythms and is present during a range of cognitive functions. However, little is known about whether and how long-range cross-frequency coupling across distant brain regions subserves working memory. Here we report that theta-slow gamma coupling between the hippocampus and medial prefrontal cortex (mPFC) is augmented in a genetic mouse model of cognitive dysfunction. This increased cross-frequency coupling is observed specifically when the mice successfully perform a spatial working memory task. In wild-type mice, increasing task difficulty by introducing a long delay or by optogenetically interfering with encoding, also increases theta-gamma coupling during correct trials. Finally, epochs of high hippocampal theta-prefrontal slow gamma coupling are associated with increased synchronization of neurons within the mPFC. These findings suggest that enhancement of theta-slow gamma coupling reflects a compensatory mechanism to maintain spatial working memory performance in the setting of increased difficulty.

Summary 22q11.2 deletion carriers show specific cognitive deficits and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A+/− mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.

To qualify as a “basic” taste quality or modality, defined as a group of chemicals that taste alike, three empirical benchmarks have commonly been used. The first is that a candidate group of tastants must have a dedicated transduction mechanism in the peripheral nervous system. The second is that the tastants evoke physiological responses in dedicated afferent taste nerves innervating the oropharyngeal cavity. Last, the taste stimuli evoke activity in central gustatory neurons, some of which may respond only to that group of tastants. Here we argue that water may also be an independent taste modality. This argument is based on the identification of a water dedicated transduction mechanism in the peripheral nervous system, water responsive fibers of the peripheral taste nerves and the observation of water responsive neurons in all gustatory regions within the central nervous system. We have described electrophysiological responses from single neurons in nucleus of the solitary tract (NTS) and parabrachial nucleus of the pons, respectively the first two central relay nuclei in the rodent brainstem, to water presented as a taste stimulus in anesthetized rats. Responses to water were in some cases as robust as responses to other taste qualities and sometimes occurred in the absence of responses to other tastants. Both excitatory and inhibitory responses were observed. Also, the temporal features of the water response resembled those of other taste responses. We argue that water may constitute an independent taste modality that is processed by dedicated neural channels at all levels of the gustatory neuraxis. Water-dedicated neurons in the brainstem may constitute key elements in the regulatory system for fluid in the body, i.e., thirst, and as part of the swallowing reflex circuitry.

Schizophrenia is caused by a diverse array of risk factors, and results in a similarly diverse set of symptoms. Electrophysiological endophenotypes lie between risks and symptoms, and have the potential to link the two. Electrophysiological studies in rodent models, described here, demonstrate that widely differing risk factors result in a similar set of core electrophysiological endophenotypes, suggesting the possibility of a shared neurobiological substrate.