James Miller

Chapter 11 Neuronal transplants used in the repair of acute ischemic injury in the central nervous system

Publisher Summary This chapter discusses whether the neurons would both integrate into host tissue and attain some measure of functional activity by reestablishing some of the normal synaptic circuitries. The chapter also assesses the ability of the transplanted neurons to attain these criteria using histological, electrophysiological and immunohistochemical (IHC) techniques. The histology demonstrates that the grafted cells appear morphologically similar to adult hippocampal neurons. Immunohistochemically, two of the prominent cell types of the hippocampal formation have been identified. calbindin-D 28K (CaBP)-like immunoreactivity that was detected in many transplanted neurons, and parvalbumin (PV)-like immunoreactivity that was also found within the grafts. The chapter concludes that neuronal transplantation techniques may have potential application in the repair of acute ischemic lesions and other forms of trauma occurring in the CNS. The injection of cell suspensions through a fine cannula is relatively nontraumatic to the overlying cortical tissue. That the transplanted neurons can aggregate into laminar-like arrangements and the observation that the transplanted regions contain both excitatory and inhibitory neurons, suggest an anatomical organization reminiscent of the normal rat CA 1 region.

Long-term potentiation facilitates behavioral responding to single-pulse stimulation of the perforant path

Three experiments were conducted to determine whether long-term potentiation (LTP) could enhance the stimulus properties of electrical brain stimulation. First, a paradigm was developed in which single-pulse stimulation of the perforant path (PP) could acquire control over operant responses. Evoked potentials were recorded from the dentate gyrus (DG) on every trial in order to measure the postsynaptic consequences of the stimulus and to monitor synaptic efficacy in the PP-DG synapses. The second experiment confirmed the relation between the amount of evoked activity and acquisition rate and also showed that transecting the PP impaired performance. In the third experiment, high-frequency stimulation of the PP produced LTP and accelerated subsequent acquisition of behavioral responding to PP stimulation. These results document a clear link between increases in synaptic efficacy and changes in behavior and thereby demonstrate the ability of LTP to serve as at least one component of the neural bases of learning and memory.

A preclinical assessment of D,L-govadine as a potential antipsychotic and cognitive enhancer

Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.l-Gov), reveals high affinity for dopamine and noradrenaline receptors, efficacy as a D2 receptor antagonist, brain penetrance in the 10-300 ng/g range, and thus motivated an assessment of the antipsychotic and pro-cognitive properties of this compound in the rat. Increased dopamine efflux in the prefrontal cortex and nucleus accumbens, measured by microdialysis, is observed following subcutaneous injection of the drug. d.l-Gov inhibits both conditioned avoidance responding (CAR) and amphetamine-induced locomotion (AIL) at lower doses than clozapine (CAR ED50: d.l-Gov 0.72 vs. clozapine 7.70 mg/kg; AIL ED50: d.l-Gov 1.70 vs. clozapine 4.27 mg/kg). Catalepsy is not detectable at low biologically relevant doses, but is observed at higher doses. Consistent with previous reports, acute d-amphetamine disrupts latent inhibition (LI) while a novel finding of enhanced LI is observed in sensitized animals. Treatment with d.l-Gov prior to conditioned stimulus (CS) pre-exposure restores LI to levels observed in controls in both sensitized animals and those treated acutely with d-amphetamine. Finally, possible pro-cognitive properties of d.l-Gov are assessed with the spatial delayed win-shift task. Subcutaneous injection of 1.0 mg/kg d.l-Gov failed to affect errors at a 30-min delay, but decreased errors observed at a 12-h delay. Collectively, these data provide the first evidence that d.l-Gov may have antipsychotic properties in conjunction with pro-cognitive effects, lending further support to the hypothesis that THPBs are a class of compounds which merit serious consideration as novel treatments for schizophrenia.