David K. Bilkey

Medial septal facilitation of hippocampal granule cell activity is mediated by inhibition of inhibitory interneurones

Rats under barbiturate anaesthesia were implanted with stimulating electrodes in the medial septal nucleus and the medial perforant path. A recording electrode and cannula were implanted in the hilus of the dentate gyrus. Electrodes were positioned so that a conditioning pulse to the medial septum, although eliciting no field potential of its own, facilitated the granule cell population spike evoked by medial perforant path stimulation. In the first experiment, the infusion into the hilus of the GABA antagonist picrotoxin was found to block the facilitation. In a second experiment, it was found that a medial septal conditioning pulse blocked recurrent inhibition of the granule cells, only if it was timed to coincide with their initial activation. We suggest that these effects are mediated through an inhibitory connection from the medial septum onto inhibitory interneurones in the dentate gyrus, and that this connection may utilize the neurotransmitter GABA.

Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Secreted amyloid precursor protein-alpha (sAPP alpha) levels are reduced during the pathogenesis of Alzheimers disease, but the significance of this for neural function is not well understood. Here, we show that intrahippocampal infusion of antibodies targeted to endogenous sAPP alpha reduced long-term potentiation (LTP) in the dentate gyrus of adult rats by approximately 50%. Conversely, infusion of recombinant sAPP alpha dose-dependently increased LTP and facilitated in vitro tetanically evoked NMDA receptor-mediated currents. Pharmacological inhibition of alpha-secretase and other a-disintegrin-and-metalloproteases by TAPI-1 reduced both LTP and tetanus-evoked NMDA receptor-mediated currents in dentate granule cells. Both effects were prevented by co-application of exogenous recombinant sAPP alpha. Similarly, spatial memory was inhibited by intrahippocampal TAPI-1, an effect that was prevented by co-application of recombinant sAPP alpha. Together these findings indicate that endogenous sAPP alpha is a key contributor to synaptic plasticity and spatial memory. Its reduced production in Alzheimers disease may thus contribute to the clinical memory deficits.

Amusia is associated with deficits in spatial processing

Amusia (commonly referred to as tone-deafness) is a difficulty in discriminating pitch changes in melodies that affects around 4% of the human population. Amusia cannot be explained as a simple sensory impairment. Here we show that amusia is strongly related to a deficit in spatial processing in adults. Compared to two matched control groups (musicians and non-musicians), participants in the amusic group were significantly impaired on a visually presented mental rotation task. Amusic subjects were also less prone to interference in a spatial stimulus-response incompatibility task and performed significantly faster than controls in an interference task in which they were required to make simple pitch discriminations while concurrently performing a mental rotation task. This indicates that the processing of pitch in music normally depends on the cognitive mechanisms that are used to process spatial representations in other modalities.

The effects of perirhinal cortical lesions on spatial reference memory in the rat

Rats with bilateral, electrolytic lesions of the perirhinal cortex and sham operated control rats were tested in the Morris water maze, a procedure which has repeatedly been shown to be sensitive to hippocampal and limbic system dysfunction. The results of the present study demonstrate that perirhinal lesioned rats were mildly impaired on this task. The lesioned animals took significantly longer than controls to locate the hidden platform during place navigation acquisition, and had significantly larger heading errors across the entire experimental procedure. In addition, these lesioned animals made fewer platform crossings than control rats during the probe trials. These results suggest that the perirhinal cortex, like the anatomically related entorhinal cortex and hippocampus, may be involved in mnemonic processing.

The effect of excitotoxic lesions centered on the hippocampus or perirhinal cortex in object recognition and spatial memory tasks.

Rats with bilateral ibotenic acid lesions centered on the hippocampus (HPC) or perirhinal cortex (PRC) and sham-operated controls were tested in a series of object recognition and spatial memory tasks. Both HPC and PRC rats displayed reduced habituation in a novel environment and were impaired in an object-location task. HPC rats were severely impaired in both the reference and working-memory versions of the water maze and radial arm maze tasks. In contrast, although PRC rats displayed mild deficits in the reference memory version of the water maze and radial arm maze tasks, they were markedly impaired in the working-memory version of both the tasks. These findings demonstrate that under certain conditions both the HPC and PRC play a role in the processing of spatial memory. Further investigation of these conditions will provide important new insights into the role of these structures in memory processes.

Immune activation during mid-gestation disrupts sensorimotor gating in rat offspring.

Maternal immune activation (MIA) is a newly developed animal model of schizophrenia. It has recently been reported that when MIA is induced with the cytokine inducer polyinosinic-polycytidilic acid (poly I:C) rats do not show deficits in prepulse inhibition (PPI), a test that is often considered a validity benchmark. The aim of the current experiment was to determine whether doses of poly I:C that have previously been shown to induce the behavioural features of schizophrenia can disrupt PPI in rats. Pregnant rat dams were given a single injection of poly I:C (4.0 mg/kg) or a saline injection equivalent on gestational day 15. Acoustic startle reactivity, habituation of the startle response and PPI were assessed in juvenile (34-35 day) and adult (>56 day) offspring. Prenatal immune activation did not alter startle reactivity on startle-only or prepulse-only trials. Furthermore, there was no effect of MIA on habituation of the startle response. MIA does however disrupt PPI, as PPI was reduced significantly in adult MIA offspring, and a trend was observed in the juvenile animals. Our finding that prenatal poly I:C can disrupt PPI in MIA rats further validates this procedure as an animal model.

Abnormal Long-Range Neural Synchrony in a Maternal Immune Activation Animal Model of Schizophrenia

The synchrony of neural firing is believed to underlie the integration of information between and within neural networks in the brain. Abnormal synchronization of neural activity between distal brain regions has been proposed to underlie the core symptomatology in schizophrenia. This study investigated whether abnormal synchronization occurs between the medial prefrontal cortex (mPFC) and the hippocampus (HPC), two brain regions implicated in schizophrenia pathophysiology, using the maternal immune activation (MIA) animal model in rats. This neurodevelopmental model of schizophrenia is induced through a single injection of the synthetic immune system activator polyriboinosinic–polyribocytidylic acid, a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection, in pregnant rat dams. It is based on epidemiological evidence of increased risk of schizophrenia in adulthood after prenatal exposure to infection. In the present study, EEG coherence and neuronal phase-locking to underlying EEG were measured in freely moving MIA and control offspring. The MIA intervention produced significant reductions in mPFC–HPC EEG coherence that correlated with decreased prepulse inhibition of startle, a measure of sensory gating and a hallmark schizotypal behavioral measure. Furthermore, changes in the synchronization of neuronal firing to the underlying EEG were evident in the theta and low-gamma frequencies. Firing within a putative population of theta-modulated, gamma-entrained mPFC neurons was also reduced in MIA animals. Thus, MIA in rats produces a fundamental disruption in long-range neuronal synchrony in the brains of the adult offspring that models the disruption of synchrony observed in schizophrenia.

Lesions of rat perirhinal cortex exacerbate the memory deficit observed following damage to the fimbria-fornix.

Rats that had received bilateral lesions of the perirhinal cortex, fimbria-fornix, combined lesions of both these structures, or sham operations were tested on an object-guided delayed non-match-to-sample task. Perirhinal lesioned and fimbria-fornix lesioned rats were moderately impaired when delay intervals of 30 s or more were introduced between the sample and test phases of the experiment. Animals with combined lesions displayed a considerably greater impairment than animals with lesions of either structure alone. The combined lesioned animals were severely impaired in the initial acquisition of the task and displayed a profound memory deficit at delay intervals of greater than 4 s. These results emphasize the importance of the perirhinal cortex to memory function and suggest that the perirhinal cortex and the hippocampal formation may function interactively in the execution of memory processes.

Induction of immediate-early gene proteins in dentate granule cells and somatostatin interneurons after hippocampal seizures

The expression of the protein products of the immediate-early genes c-fos, Fos B, Fos-related proteins (FRAs), c-jun, jun B, jun D and krox-24 was investigated in the rat hippocampus at various times after electrically-induced hippocampal seizures. Hippocampal seizures induced all the immediate-early gene proteins in dentate granule cells with differing time-courses. In addition, Krox-24, Fos and Jun D were also induced in somatostatin-containing interneurons throughout the hippocampus and also in a small percentage of parvalbumin-containing interneurons. Thus, hippocampal seizures induce waves of immediate-early gene protein expression in dentate granule cells and a selective expression of krox-24, Fos and Jun D in hippocampal somatostatin interneurons. These results suggest that biochemical and/or morphological changes occurring in dentate granule cells and somatostatin interneurons after seizures may be regulated by immediate-early gene expression, and that these immediate-early gene proteins may be involved in seizure development in the nervous system.

Perirhinal cortex lesions in rats disrupt performance in a spatial DNMS task.

Rats with bilateral electrolytic lesions of the perirhinal cortex and sham operated control rats were tested in a spatially guided, delayed non match to sample task. Although perirhinal lesioned animals showed no deficit in acquisition of the task, a performance deficit was observed across longer delay intervals. These results indicate that the perirhinal cortex is a critical component of the network subserving working or declarative memory in the rat.